Human antibody targeting Crimean-Congo hemorrhagic fever virus glycoprotein 38 protects mice against heterologous virus challenge
Nathaniel S. Chapman, Viktoriya Borisevich, Nurgun Kose, Luke Myers, Stephen Priest, Éric Bergeron, Elena Trigo Esteban, María Paz Sánchez-Seco, José Melero, Thomas W. Geisbert, Robert W. Cross, James E. Crowe Jr.
Nathaniel S. Chapman, Viktoriya Borisevich, Nurgun Kose, Luke Myers, Stephen Priest, Éric Bergeron, Elena Trigo Esteban, María Paz Sánchez-Seco, José Melero, Thomas W. Geisbert, Robert W. Cross, James E. Crowe Jr.
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Research Article Infectious disease Virology

Human antibody targeting Crimean-Congo hemorrhagic fever virus glycoprotein 38 protects mice against heterologous virus challenge

Abstract

Crimean-Congo hemorrhagic fever virus (CCHFV) is an emerging arboviral and zoonotic bunyavirus. CCHFV can infect livestock, wild animals, and humans. Here, we report the isolation of a panel of mAbs from the B cells of an immune individual following a natural nosocomial infection. We determined that the panel comprised antibodies that bound to 2 glycoproteins: (a) the carboxy-terminal glycoprotein (Gc) that serves as the fusion protein and (b) the glycoprotein 38 (GP38). By antibody variable gene analysis, we identified genetic diversity in the B cell response to CCHFV within a single donor for both Gc- and GP38-specific responses. Protection against most bunyavirus-associated diseases is mediated principally by neutralizing antibodies, but here, we found that neutralization activity was not associated with protection. Gc-specific antibodies to diverse antigenic sites neutralized only weakly and did not protect against heterologous virus challenge. GP38-specific antibodies bound to 2 dominant antigenic sites on the glycoprotein. Although GP38-specific antibodies did not neutralize the virus, one mediated protection against heterologous virus challenge in an experimental model of infection in mice primarily by complement-mediated activity. These studies support the development of protective CCHFV countermeasures against GP38.

Authors

Nathaniel S. Chapman, Viktoriya Borisevich, Nurgun Kose, Luke Myers, Stephen Priest, Éric Bergeron, Elena Trigo Esteban, María Paz Sánchez-Seco, José Melero, Thomas W. Geisbert, Robert W. Cross, James E. Crowe Jr.

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Figure 7

PreGn-identifying antibodies compete with reference mouse monoclonal antibodies to GP38 and other preGn binding human antibodies.

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PreGn-identifying antibodies compete with reference mouse monoclonal ant...
PreGn binding antibodies were added to preGn-expressing cells at saturating concentrations (20 μg/mL) for 30 minutes. Alexa Fluor 647–conjugated mouse or human antibodies were then added to cells at 5 μg/mL without a prior wash step. Cells were washed and immediately processed on an iQue flow cytometer. The values shown are the percentage of binding that occurred during competition compared with noncompeted binding of the mAb. This value was normalized to 100%. The values are also indicated by the dotted lines; above 40% indicated no competition, between 40% and 20% indicated partial competition, and below 20% indicated competition. Values shown are from 2 independent experiments with 3 replicates. Data represent mean ± SD.