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

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. [Display omitted] •361 monoclonal antibodies against CCHFV glycoproteins isolated from human survivors•Potent and broad neutralizers targeting six antigenic sites in Gc identified•Specific combinations of noncompeting antibodies afford synergistic neutralization•Bispecific antibody combining synergistic antibodies confers therapeutic protection By isolating monoclonal antibodies against Crimean-Congo hemorrhagic fever virus glycoproteins from human survivors, Fels et al. were able to identify combinations of synergistic neutralizing antibodies and engineer bispecific antibodies that provide therapeutic protection.