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 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. A human monoclonal antibody directed to the GP38 protein of Crimean-Congo hemorrhagic fever virus (CCHFV) does not neutralize the virus but mediates protection against heterologous virus challenge in an experimental model of infection in mice. The studies reveal novel aspects of mechanisms of bunyavirus immunity.