Structure of trimeric pre-fusion rabies virus glycoprotein in complex with two protective antibodies

Rabies virus (RABV) causes lethal encephalitis and is responsible for approximately 60,000 deaths per year. As the sole virion-surface protein, the rabies virus glycoprotein (RABV-G) mediates host-cell entry. RABV-G’s pre-fusion trimeric conformation displays epitopes bound by protective neutralizing antibodies which can be induced by vaccination or passively administered for post-exposure prophylaxis. We report a 2.8-Å structure of a RABV-G trimer in the pre-fusion conformation, in complex with two neutralizing and protective monoclonal antibodies, 17C7 and 1112-1. One of these antibodies is a licensed prophylactic (17C7, Rabishield), which we show locks the protein in pre-fusion conformation. We demonstrate that targeted mutations can stabilize RABV-G in the pre-fusion conformation, a key step towards structure-guided vaccine design. These data reveal the higher-order architecture of a key therapeutic target and the structural basis of neutralization by antibodies binding two key antigenic sites, and will facilitate the development of improved vaccines and prophylactic antibodies. ### Competing Interest Statement SF and ADD are named inventors on a patent invention relating to stabilization of RABV-G by the H270P mutation.