1. Mutating a flexible region of the RSV F protein can stabilize the prefusion conformation.
- Author
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Liang Y, Shao S, Li XY, Zhao ZX, Liu N, Liu ZM, Shen FJ, Zhang H, Hou JW, Zhang XF, Jin YQ, Du LF, Li X, Zhang J, Su JG, and Li QM
- Subjects
- Animals, Humans, Mice, Antibodies, Neutralizing immunology, Antibodies, Viral immunology, Cryoelectron Microscopy, Immunogenicity, Vaccine, Lung virology, Mice, Inbred BALB C, Mutagenesis, Mutation, Protein Conformation, Protein Stability, Respiratory Syncytial Virus Infections immunology, Respiratory Syncytial Virus Infections prevention & control, Respiratory Syncytial Virus Vaccines immunology, Respiratory Syncytial Virus Vaccines chemistry, Respiratory Syncytial Virus Vaccines genetics, Respiratory Syncytial Virus, Human genetics, Respiratory Syncytial Virus, Human immunology, Viral Fusion Proteins chemistry, Viral Fusion Proteins immunology, Viral Fusion Proteins genetics
- Abstract
The respiratory syncytial virus (RSV) fusion (F) glycoprotein is highly immunogenic in its prefusion (pre-F) conformation. However, the protein is unstable, and its conformation must be stabilized for it to function effectively as an immunogen in vaccines. We present a mutagenesis strategy to arrest the RSV F protein in its pre-F state by blocking localized changes in protein structure that accompany large-scale conformational rearrangements. We generated a series of mutants and screened them in vitro to assess their potential for forming a stable pre-F. In animals, the immunogenicity of a representative mutant F protein, with a conformation confirmed by cryo-electron microscopy, elicited levels of neutralizing antibodies and protection against RSV-induced lung damage that were comparable to those of DS-Cav1, a pre-F used in a licensed vaccine.
- Published
- 2024
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