Systematic Analysis of Monoclonal Antibodies against Ebola Virus GP Defines Features that Contribute to Protection.
Saphire EO., Schendel SL., Fusco ML., Gangavarapu K., Gunn BM., Wec AZ., Halfmann PJ., Brannan JM., Herbert AS., Qiu X., Wagh K., He S., Giorgi EE., Theiler J., Pommert KBJ., Krause TB., Turner HL., Murin CD., Pallesen J., Davidson E., Ahmed R., Aman MJ., Bukreyev A., Burton DR., Crowe JE., Davis CW., Georgiou G., Krammer F., Kyratsous CA., Lai JR., Nykiforuk C., Pauly MH., Rijal P., Takada A., Townsend AR., Volchkov V., Walker LM., Wang C-I., Zeitlin L., Doranz BJ., Ward AB., Korber B., Kobinger GP., Andersen KG., Kawaoka Y., Alter G., Chandran K., Dye JM., Viral Hemorrhagic Fever Immunotherapeutic Consortium None.
Antibodies are promising post-exposure therapies against emerging viruses, but which antibody features and in vitro assays best forecast protection are unclear. Our international consortium systematically evaluated antibodies against Ebola virus (EBOV) using multidisciplinary assays. For each antibody, we evaluated epitopes recognized on the viral surface glycoprotein (GP) and secreted glycoprotein (sGP), readouts of multiple neutralization assays, fraction of virions left un-neutralized, glycan structures, phagocytic and natural killer cell functions elicited, and in vivo protection in a mouse challenge model. Neutralization and induction of multiple immune effector functions (IEFs) correlated most strongly with protection. Neutralization predominantly occurred via epitopes maintained on endosomally cleaved GP, whereas maximal IEF mapped to epitopes farthest from the viral membrane. Unexpectedly, sGP cross-reactivity did not significantly influence in vivo protection. This comprehensive dataset provides a rubric to evaluate novel antibodies and vaccine responses and a roadmap for therapeutic development for EBOV and related viruses.