Antibodies from a Human Survivor Define Sites of Vulnerability for Broad Protection against Ebolaviruses

Area of Science:

• Virology
• Immunology
• Drug Discovery

Background:

• Experimental monoclonal antibody (mAb) therapies show promise for Ebola virus (EBOV) infections.
• Species-specific recognition of the viral glycoprotein (GP) limits current mAb efficacy against divergent ebolaviruses.
• There is a need for broadly effective immunotherapeutics against multiple ebolaviruses.

Purpose of the Study:

• To identify monoclonal antibodies (mAbs) with potent pan-ebolavirus neutralizing activity.
• To investigate the epitope and mechanism of action for broadly neutralizing mAbs.
• To inform the development of effective immunotherapeutics and vaccines against filoviruses.

Main Methods:

• Mining the human immune response to natural EBOV infection.
• Characterization of mAb binding and neutralization activity against diverse ebolaviruses.
• Epitope mapping and analysis of GP structure and function.

Main Results:

• Identified mAbs with potent neutralizing activity and protective efficacy against three virulent ebolaviruses.
• Discovered that these mAbs recognize an inter-protomer epitope in the GP fusion loop.
• Demonstrated neutralization by targeting a proteolytically primed GP intermediate (GP_CL) in endosomes.

Conclusions:

• Broadly neutralizing mAbs can be elicited with few somatic hypermutations, suggesting efficient development.
• Optimized GP immunogens could enhance the generation of such antibodies.
• Findings support the development of broadly effective immunotherapeutics and vaccines against filoviruses.