Multimeric single-domain antibody complexes protect against bunyavirus infections

Wichgers Schreur, Paul J.; van de Water, Sandra; Harmsen, Michiel; Bermúdez-Méndez, Erick; Drabek, Dubravka; Grosveld, Frank; Wernike, Kerstin; Beer, Martin; Aebischer, Andrea; Daramola, Olalekan; Conde, Sara Rodriguez; Brennan, Karen; Kozub, Dorota; Kristiansen, Maiken Søndergaard; Mistry, Kieran K.; Deng, Ziyan; Hellert, Jan; Guardado-Calvo, Pablo; Rey, Félix A.; van Keulen, Lucien; Kortekaas, Jeroen


The World Health Organization has included three bunyaviruses posing an increasing threat to human health on the Blueprint list of viruses likely to cause major epidemics and for which no, or insufficient countermeasures exist. Here, we describe a broadly applicable strategy, based on llama-derived single-domain antibodies (VHHs), for the development of bunyavirus biotherapeutics. The method was validated using the zoonotic Rift Valley fever virus (RVFV) and Schmallenberg virus (SBV), an emerging pathogen of ruminants, as model pathogens. VHH building blocks were assembled into highly potent neutralizing complexes using bacterial superglue technology. The multimeric complexes were shown to reduce and prevent virus-induced morbidity and mortality in mice upon prophylactic administration. Bispecific molecules engineered to present two different VHHs fused to an Fc domain were further shown to be effective upon therapeutic administration. The presented VHH-based technology holds great promise for the development of bunyavirus antiviral therapies.