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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月6日

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  • Dawid S. Zyla,
  • Roberta Della Marca,
  • Davide Lacarbonara,
  • Gele Niemeyer,
  • Gillian Zipursky,
  • Laura Di Clemente,
  • Mare H. L. Verbruggen,
  • Laura L. A. van Dijk,
  • Oscar Martinez Ceh,
  • Gabriella Jonathan-Trakht,
  • Gavreel Kalantarov,
  • Marissa Acciani,
  • Giulia Laterza,
  • Dariia Vyshenska,
  • Cameron Leedale,
  • Emily Pawlack,
  • Kathryn M. Hastie,
  • Branka Horvat,
  • Rik L. de Swart,
  • Rory D. de Vries,
  • Alexander L. Greninger,
  • Stefan Niewiesk,
  • Erica Ollmann Saphire,
  • Matteo Porotto

摘要

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.