Structure-based design of a fusion glycoprotein vaccine for respiratory syncytial virus.
Structure-based design of a fusion glycoprotein vaccine for respiratory syncytial virus.
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DOI：
10.1126/science.1243283
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发表时间：
2013-11-01
期刊：
影响因子：
--
通讯作者：
Kwong PD
中科院分区：
文献类型：
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作者：
McLellan JS;Chen M;Joyce MG;Sastry M;Stewart-Jones GB;Yang Y;Zhang B;Chen L;Srivatsan S;Zheng A;Zhou T;Graepel KW;Kumar A;Moin S;Boyington JC;Chuang GY;Soto C;Baxa U;Bakker AQ;Spits H;Beaumont T;Zheng Z;Xia N;Ko SY;Todd JP;Rao S;Graham BS;Kwong PD
呼吸道合胞病毒 (RSV) 是五岁以下儿童住院的主要原因。我们试图设计一种病毒抗原，提供比现有疫苗更好的保护，并专注于抗原位点 Ø，这是一个针对 RSV 融合 (F) 糖蛋白融合前状态的亚稳态位点，因为该位点是极强的 RSV 中和抗体的目标。基于结构的设计产生了 RSV F 的稳定版本，当暴露于极端 pH、重量克分子渗透压浓度和温度时，该版本仍能保持抗原位点 Ø。六个 RSV F 晶体结构提供了关于引入半胱氨酸残基和填充疏水空腔如何提高稳定性的原子级数据。在小鼠和猕猴中使用 RSV F 位点稳定的变体进行免疫，可引发 RSV 特异性中和活性水平，其水平是保护阈值的许多倍。
Respiratory syncytial virus (RSV) is the leading cause of hospitalization for children under five years of age. We sought to engineer a viral antigen that provides greater protection than currently available vaccines and focused on antigenic site Ø, a metastable site specific to the prefusion state of the RSV fusion (F) glycoprotein, as this site is targeted by extremely potent RSV-neutralizing antibodies. Structure-based design yielded stabilized versions of RSV F that maintained antigenic site Ø when exposed to extremes of pH, osmolality, and temperature. Six RSV F-crystal structures provided atomic-level data on how introduced cysteine residues and filled hydrophobic cavities improved stability. Immunization with site Ø-stabilized variants of RSV F in mice and macaques elicited levels of RSV-specific neutralizing activity many times the protective threshold.