Structural Basis of Broad Ebolavirus Neutralization by a Human Survivor Antibody

Brandyn R. West, Anna Z. Wec, Crystal L. Moyer, Marnie L. Fusco, Philipp A. Ilinykh, Kai Huang, Ariel S. Wirchnianski, Rebekah M. James, Andrew S. Herbert, Sean Hui, Eileen Goodwin, Katie A. Howell, Shweta Kailasan, M. Javad Aman, Laura M. Walker, John M. Dye, Alexander Bukreyev, Kartik Chandran, Erica Ollmann Saphire 

Nature Structural & Molecular Biology 26, 204–212. DOI: 10.1038/s41594-019-0191-4

Overview 

Existing ebolavirus antibody therapies only treat infection with Ebola virus (EBOV) itself but are ineffective against related ebolaviruses, such as Sudan virus (SUDV). This deficiency matters because no treatments exist for SUDV outbreaks. The key obstacle for generating broadly neutralizing antibodies (bnAbs) stems from limited amino acid sequence conservation within the surface glycoproteins of ebolaviruses. However, antibodies that target the functional, conserved viral fusion machinery offer a promising route to broad, protective therapies. This study solved the crystal structure of ADI-15946, a bnAb isolated from a survivor of the 2013–2016 EBOV outbreak, bound to the viral glycoprotein, revealing how it achieves cross-reactivity and enabling structure-guided engineering to extend its activity to SUDV. 

Study rationale and objectives 

ADI-15946 is known to potently neutralize EBOV and Bundibugyo virus (BDBV) but not SUDV, and prior low-resolution imaging suggested it binds a distinct site on the glycoprotein compared to other known broadly neutralizing antibodies. The study aimed to define the structural basis of the activity of ADI-15946 against its target antigen, identifying the features of its binding site and antibody-binding regions that confer broad reactivity, and investigating why that reactivity does not extend to SUDV with the goal of enabling rational, structure-guided design to confer broader neutralization. 

The objectives of the study were to: 

Solve the crystal structure of ADI-15946 bound to EBOV glycoprotein to define its epitope and mechanism of neutralization. 

• Determine why the parental antibody has reduced neutralization activity against SUDV. 

• Engineer the antibody to improve SUDV neutralization without losing activity against EBOV and BDBV. 

Approach and techniques 

The structure of ADI-15946 bound to cleaved EBOV glycoprotein was solved and compared to the glycoprotein’s own internal contacts. The team then tested how viral processing and a second complementary antibody affected exposure of the binding site, and used the structural data to guide targeted mutations aimed at broadening activity.  

Major findings and results 

• ADI-15946 binds a conserved pocket on the glycoprotein by mimicking a natural intramolecular contact, blocking the conformational changes required for membrane fusion. 

• Both natural viral processing and binding of a second, non-neutralizing antibody increased epitope exposure, boosting ADI-15946 potency. This suggests antibody combinations could work synergistically. 

• Structural mapping explained the weak activity of ADI-15946 against SUDV, and a small set of guided mutations improved SUDV binding and neutralization while preserving activity against EBOV and BDBV. 

Implications for therapeutic antibody development 

In-depth characterization of known broadly neutralizing antibodies is critical to designing next-generation antibody cocktails and vaccines that elicit broadly protective responses. This work demonstrates the value of structural characterization for understanding and expanding the breadth of broadly neutralizing antibodies. The authors note that further work is needed to confirm the SUDV-enhanced antibody variants have favorable pharmacokinetics and protective efficacy in vivo. They also propose that future vaccine immunogens designed to expose this and other conserved, cryptic epitopes could elicit broadly neutralizing antibodies like ADI-15946 more effectively. 

Addendum: Several of the study’s authors and affiliated labs later contributed to the pan-ebolavirus antibody cocktail MBP134 (not mentioned in this paper).