Problem

For many infectious disease targets, neutralization is often the primary means by which antibody candidates are selected for clinical development. However, as with the mounting importance of extra-neutralizing antibody functions in vaccine-mediated protection from infection, extra-neutralizing antibody functions are increasingly recognized as critical in monoclonal antibody–mediated protection from infection. In numerous studies with both individual antibodies and cocktails of antibodies, non-neutralizing antibodies have demonstrated protection in animal models of Ebola virus infection. Coupled with the observation that not all neutralizing antibodies are protective, this suggests that neutralization activity is neither necessary nor sufficient for protection in vivo. However, defining the functions of EBOV-specific monoclonal antibodies that are linked to protection had proven difficult. As part of the Viral Hemorrhagic Fever Immunotherapeutics Consortium, Systems Serology was used to profile almost 170 Ebola-specific monoclonal antibodies to define the antibody features and functions critical to protection.

Systems Serology Application

While neutralizing activity was clearly linked with protection, analysis of antibody effector functions suggested a role for additional Ab functions in protection. Critically, for monoclonal antibodies with limited neutralizing activity, increased extra-neutralizing antibody functions were associated with protection in vivo. In particular, the ability of antibodies to induce phagocytosis and activate NK cells were particularly important for protection by non-neutralizing antibodies. Furthermore, neutralizing antibodies that lacked the ability to induce phagocytosis were less protective in vivo, suggesting that neutralization may not be the critical functional activity underlying protection in vivo. Similar observations have been observed in HIV and influenza infection, further highlighting the importance of extra-neutralizing antibody functions in monoclonal antibody–mediated protection. Ultimately, the data generated from this study provides a critical framework to both define and exploit immune correlates of protection to rationally guide the development of effective therapeutics against Ebola virus and other human pathogens.