A highly stable prefusion RSV F vaccine derived from structural analysis of the fusion mechanism.
A highly stable prefusion RSV F vaccine derived from structural analysis of the fusion mechanism.
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DOI：
10.1038/ncomms9143
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发表时间：
2015-09-03
影响因子：
16.6
通讯作者：
Langedijk JPM
中科院分区：
文献类型：
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作者：
Krarup A;Truan D;Furmanova-Hollenstein P;Bogaert L;Bouchier P;Bisschop IJM;Widjojoatmodjo MN;Zahn R;Schuitemaker H;McLellan JS;Langedijk JPM
呼吸道合胞病毒（RSV）引起急性下呼吸道感染，是婴儿住院的主要原因。最近，一种基于稳定在天然融合前构象的 RSV 融合蛋白 (RSV F) 的有前途的疫苗抗原已被描述。在这里，我们报告了基于防止第一重折叠区域铰链运动和消除融合肽的蛋白水解暴露的将 RSV F 阻留在融合前构象的替代策略。已鉴定出有限数量的独特突变，可稳定 RSV F 的融合前构象并显着提高表达水平。这种高度稳定的预融合 RSV F 可在棉鼠体内引发中和抗体，并诱导针对病毒攻击的完全保护。此外，融合前变体的结构和生化分析表明p27的功能，p27是多肽链中融合肽之前的切除片段。 呼吸道合胞病毒（RSV）是一种高度传染性的儿童呼吸道病原体，目前尚无疫苗可用。在此，作者提出了一种将 RSV F 蛋白稳定在融合前构象的策略，该策略可以在动物模型中引发强烈的保护性免疫反应。
Respiratory syncytial virus (RSV) causes acute lower respiratory tract infections and is the leading cause of infant hospitalizations. Recently, a promising vaccine antigen based on the RSV fusion protein (RSV F) stabilized in the native prefusion conformation has been described. Here we report alternative strategies to arrest RSV F in the prefusion conformation based on the prevention of hinge movements in the first refolding region and the elimination of proteolytic exposure of the fusion peptide. A limited number of unique mutations are identified that stabilize the prefusion conformation of RSV F and dramatically increase expression levels. This highly stable prefusion RSV F elicits neutralizing antibodies in cotton rats and induces complete protection against viral challenge. Moreover, the structural and biochemical analysis of the prefusion variants suggests a function for p27, the excised segment that precedes the fusion peptide in the polypeptide chain. Respiratory syncytial virus (RSV) is a highly contagious childhood pathogen of the respiratory tract for which no vaccine is currently available. Here the authors present a strategy to stabilize the RSV F protein in a prefusion conformation that can elicit a strong protective immune response in animal models.