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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.

SUBMITTER: Fels JM

PROVIDER: S-EPMC8559771 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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

Fels J Maximilian JM Maurer Daniel P DP Herbert Andrew S AS Wirchnianski Ariel S AS Vergnolle Olivia O Cross Robert W RW Abelson Dafna M DM Moyer Crystal L CL Mishra Akaash K AK Aguilan Jennifer T JT Kuehne Ana I AI Pauli Noel T NT Bakken Russell R RR Nyakatura Elisabeth K EK Hellert Jan J Quevedo Gregory G Lobel Leslie L Balinandi Stephen S Lutwama Julius J JJ Zeitlin Larry L Geisbert Thomas W TW Rey Felix A FA Sidoli Simone S McLellan Jason S JS Lai Jonathan R JR Bornholdt Zachary A ZA Dye John M JM Walker Laura M LM Chandran Kartik K

Cell 20210601 13

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 w ...[more]

PMID: 34077751

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Project description:Crimean-Congo hemorrhagic fever virus (CCHFV) is a cause of severe hemorrhagic fever. Its tick reservoir and vector are widely distributed throughout Africa, Southern and Eastern Europe, the Middle East, and Asia. Serological evidence suggests that CCHFV can productively infect a wide variety of species, but only humans develop severe, sometimes fatal disease. The role of the host adaptive immunity in control or contribution to the severe pathology seen in CCHF cases is largely unknown. Studies of adaptive immune responses to CCHFV have been limited due to lack of suitable small animal models. Wild-type mice are resistant to CCHFV infection, and type I interferon-deficient mice typically develop a rapid-onset fatal disease prior to development of adaptive immune responses. We report here a mouse model in which type I interferon-deficient mice infected with a clinical isolate of CCHFV develop a severe inflammatory disease but ultimately recover. Recovery was coincident with development of CCHFV-specific B- and T-cell responses that were sustained for weeks postinfection. We also found that recovery from a primary CCHFV infection could protect against disease following homologous or heterologous reinfection. Together this model enables study of multiple aspects of CCHFV pathogenesis, including convalescence, an important aspect of CCHF disease that existing mouse models have been unsuitable for studying.IMPORTANCE The role of antibody or virus-specific T-cell responses in control of acute Crimean-Congo hemorrhagic fever virus infection is largely unclear. This is a critical gap in our understanding of CCHF, and investigation of convalescence following severe acute CCHF has been limited by the lack of suitable small animal models. We report here a mouse model of CCHF in which infected mice develop severe disease but ultimately recover. Although mice developed an inflammatory immune response along with severe liver and spleen pathology, these mice also developed CCHFV-specific B- and T-cell responses and were protected from reinfection. This model provides a valuable tool to investigate how host immune responses control acute CCHFV infection and how these responses may contribute to the severe disease seen in CCHFV-infected humans in order to develop therapeutic interventions that promote protective immune responses.

Dataset Information

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

Publications

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

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