Antibody treatment of Ebola and Sudan virus infection via a uniquely exposed epitope within the glycoprotein receptor-binding site

Howell, Katie A.; Qiu, Xiangguo; Brannan, Jennifer M.; Bryan, Christopher; Davidson, Edgar; Holtsberg, Frederick W.; Wec, Anna Z.; Shulenin, Sergey; Biggins, Julia E.; Douglas, Robin; Enterlein, Sven G.; Turner, Hannah L.; Pallesen, Jesper; Murin, Charles D.; He, Shihua; Kroeker, Andrea; Vu, Hong; Herbert, Andrew S.; Fusco, Marnie L.; Nyakatura, Elisabeth K.; Lai, Jonathan R.; Keck, Zhen-Yong; Foung, Steven K. H.; Saphire, Erica Ollmann; Zeitlin, Larry; Ward, Andrew B.; Chandran, Kartik; Doranz, Benjamin J.; Kobinger, Gary P.; Dye, John M.; Aman, M. Javad

Previous efforts to identify cross-neutralizing antibodies to the receptor binding site (RBS) of ebolavirus glycoproteins have been unsuccessful, largely because the RBS is occluded on the viral surface. We report a monoclonal antibody (FVM04) that targets a uniquely exposed epitope within the RBS, cross-neutralizes Ebola (EBOV), Sudan (SUDV), and to a lesser extent Bundibugyo viruses, and shows protection against EBOV and SUDV in mice and guinea pigs. The antibody cocktail ZMappâ„¢, is remarkably effective against EBOV (Zaire), but does not cross-neutralize other ebolaviruses. By replacing one of the ZMappâ„¢ components with FVM04, we retained the anti-EBOV efficacy while extending the breadth of protection to SUDV, thereby generating a cross protective antibody cocktail. In addition, we report several mutations at the base of the ebolavirus glycoprotein that enhance the binding of FVM04 and other cross-reactive antibodies. These findings have important implications for pan-ebolavirus vaccine development and defining broadly protective antibody cocktails.