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.

中文翻译：

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突变 RSV F 蛋白的柔性区域可以稳定融合前构象


呼吸道合胞病毒 (RSV) 融合 (F) 糖蛋白在其融合前 (pre-F) 构象中具有高度免疫原性。然而，该蛋白质不稳定，其构象必须稳定才能有效地充当疫苗中的免疫原。我们提出了一种诱变策略，通过阻止伴随大规模构象重排的蛋白质结构的局部变化，将 RSV F 蛋白阻止在 F 前状态。我们生成了一系列突变体并在体外对其进行筛选，以评估它们形成稳定的前F的潜力。在动物中，代表性突变 F 蛋白的免疫原性（其构象已通过冷冻电子显微镜证实）引发了中和抗体水平，并能防止 RSV 诱导的肺损伤，其水平与 DS-Cav1（使用的前 F）相当。在获得许可的疫苗中。