Antigenic landscape of rabies and related lyssaviruses revealed by cryo-EM

Rabies continues to kill over 60,000 people per year despite life-saving vaccines and post-exposure treatments, and costs billions of dollars in prevention and treatment. Preventing rabies deaths and reducing the global economic burden of the virus will require both developing a monoclonal antibody cocktail to replace human serum in treatment and improving rabies vaccines to elicit long-lasting protection. Here, we solve nine cryo-EM structures of neutralizing monoclonal antibodies in complex with the rabies virus surface glycoprotein (RABV-G). The nine structures span three known antigenic sites plus two new antigenic sites, not previously mapped. We further find that these two new sites are the targets of antibodies with the desired broad neutralization of rabies as well as other emerging lyssaviruses. Across the mAb panel, fusion inhibition and binding affinity correlate best with neutralization. Together, these results provide a roadmap for structure-guided vaccine and therapeutic antibody design for rabies and related lyssaviruses.