Structural and mechanistic basis for antibody neutralization of the measles fusion protein.

Abstract

Measles virus (MeV) is a highly contagious pathogen and a major global health threat. Resurgent infections, driven by insufficient vaccine coverage, waning herd immunity, and the vulnerability of immunocompromised populations, highlight the urgent need for effective countermeasures. While most vaccine-elicited antibodies target the hemagglutinin (H) protein, antibodies against the fusion (F) protein are also potent inhibitors. However, the specific target sites on this class I fusion protein, which undergoes dramatic conformational changes during entry, remain insufficiently characterized. Here, we characterize four mAbs targeting distinct F conformations. Structural analyses map antibody interactions, revealing that three neutralizing mAbs recognize the metastable prefusion conformation, while a non-neutralizing mAb binds only the post-triggered state. Biophysical and functional assays define distinct mechanisms of action: neutralization occurs either by stabilizing the prefusion protein or by preventing the extended intermediate from completing fusion. Uniquely, we detect a novel mechanism where an antibody prematurely triggers F activation but blocks the subsequent refolding required for viral entry. These findings provide the first detailed mapping of neutralizing epitopes on MeV F, establishing a framework for the rational design of F-targeted interventions.