Structure of the rabies virus glycoprotein trimer bound to a pre-fusion specific neutralizing antibody

Rabies infection is nearly 100% lethal if untreated and kills over 50,000 people annually, many of them children. Existing rabies vaccines target the rabies virus glycoprotein (RABV-G) but generate short-lived immune responses, likely because the protein is heterogeneous under physiological conditions. Here, we report the 3.39Å cryo-EM structure of trimeric, pre-fusion RABV-G complexed with RVA122, a potently neutralizing human antibody. RVA122 binds to a quaternary epitope at the top of RABV-G, bridging domains and stabilizing RABV-G protomers in a prefusion state. RABV-G trimerization involves side-to-side interactions between the central α-helix and adjacent loops, rather than contacts between central helices, and interactions among the fusion loops at the glycoprotein base. These results provide a basis to develop improved rabies vaccines based on RABV-G stabilized in the prefusion conformation. One sentence summary We report the structure and trimeric interface of pre-fusion rabies virus glycoprotein bound to the neutralizing antibody RVA122. ### Competing Interest Statement D.C. and H.B. hold patents on the use of monoclonal antibodies against rabies virus: PCT/EP2019/078439 Antibodies and methods for the treatment of lyssavirus infection; and PCT/EP2014/003076 Antibodies that potentially neutralize rabies virus and other lyssaviruses and uses thereof. D.C. is employee of Vir Biotechnology and may hold shares in Vir Biotechnology.