Science2013-11-02 6:30 AM

Structure-Based Design of a Fusion Glycoprotein Vaccine for Respiratory Syncytial Virus 儿童呼吸道合胞体病毒的融合糖蛋白疫苗的结构设计

Abstract Respiratory syncytial virus (RSV) is the leading cause of hospitalization for children under 5 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. 论文摘要 RSV:儿童呼吸道合胞体病毒 RSV F : 儿童呼吸道合胞体病毒融合物 Antigenic site: 抗原位点或者抗原结合位点 儿童呼吸道合胞体病毒是5岁以下儿童住院的首要原因。 我们设法制造出一种能够比我们现在已有的疫苗提供更好保护的新的疫苗。这个疫苗设计重点在于抗原位点Ø, 抗原位点Ø是融合前的RSV融合蛋白上的一个不太稳定的抗原位点,并且它是RSV中和抗体反应发生时抗体绝对瞄准的一个抗原位点。 基于结构的设计制造出了RSV融合物的稳定版本,这个版本使得抗原位点Ø即使暴露在极端的PH环境,渗透压和温度下仍可以保持稳定。6RSV融合物结晶体结构提供关于如果产生半胱氨酸(cysteine :一种晶状氨基酸)残留物以及如何使得疏水腔更稳定的原子级别的数据。 给小鼠和猕猴进行具有稳定原位点Ø的RSV融合物疫苗接种后发现RSV中和抗体反应的保护值成倍提高。 Editor's Summary Designer Vaccine Respiratory syncytial virus (RSV) is one of the last remaining childhood diseases without an approved vaccine. Using a structure-based approach, McLellan et al. (p. 592) designed over 150 fusion glycoprotein variants, assessed their antibody reactivity, determined crystal structures of stabilized variants, and measured their ability to elicit protective responses. This approach yielded an immunogen that elicits higher protective responses than the postfusion form of the fusion glycoprotein, which is one of the current leading RSV vaccine candidates entering clinical trials. Importantly, highly protective responses were elicited in both mice and macaques. 编辑总结: 设计师疫苗 儿童呼吸道合胞病毒是最后一批没有确定疫苗的儿童疾病病毒之一。 使用基于结构的方法,麦克莱伦设计了超过150种融合糖蛋白变种, 评估他们的抗体反应, 确定稳定的变种晶体结构,并测定它们引起保护性反应的能力。 应用这个方法制造的免疫原比融合后形成的融合糖蛋白引发更高的保护反应, 这是一个当前领先的进入临床测试的RSV候选疫苗。 更重要的是,疫苗在小鼠和猕猴身上引发了高度的保护性反应。

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