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

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 monoclonal antibodies (mAbs) from the B cells of an immune individual following a natural nosocomial infection. We determined that the panel comprised antibodies that bound to two glycoproteins: 1) the carboxy-terminal glycoprotein (Gc) that serves as the fusion protein and 2) 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 two 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 model of development of CCHFV countermeasures that induce protection against GP38 in vivo.