Searching for an ideal vaccine candidate among different MERS coronavirus receptor-binding fragments--the importance of immunofocusing in subunit vaccine design.
Searching for an ideal vaccine candidate among different MERS coronavirus receptor-binding fragments--the importance of immunofocusing in subunit vaccine design.
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DOI：
10.1016/j.vaccine.2014.08.086
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发表时间：
2014-10-21
期刊：
影响因子：
5.5
通讯作者：
Du, Lanying
中科院分区：
文献类型：
--
作者：
Ma, Cuiqing;Wang, Lili;Tao, Xinrong;Zhang, Naru;Yang, Yang;Tseng, Chien-Te K.;Li, Fang;Zhou, Yusen;Jiang, Shibo;Du, Lanying
我们表达跨越S350-588、358-588、367-588、377-606和377-588的五个MERS-CoV RBD。S377-588、367-588和358-588的受体结合能力最强。S377-588和367-588在小鼠中诱导最高滴度的IgG抗体。S377-588在小鼠中具有最高中和性，在兔中具有高中和性。S377-588含有稳定折叠的RBD结构和主要的中和表位。新出现的中东呼吸综合征冠状病毒（MERS-CoV）目前正在人类中传播，因此开发有效的MERS疫苗成为当务之急。MERS-CoV刺突蛋白中定义的受体结合结构域（RBD）可以潜在地作为针对MERS-CoV感染的亚单位疫苗候选物。为了鉴定理想的疫苗候选物，我们构建了五种不同版本的RBD片段，S350-588-Fc、S358-588-Fc、S367-588-Fc、S367-606-Fc和S377-588-Fc（它们的名称表示它们在刺突蛋白中的残基范围和它们的C-末端Fc标签），并进一步研究了它们的受体结合亲和力、抗原性、免疫原性，和中和电位。结果显示，S377-588-Fc是在小鼠中表现出最高DPP 4结合亲和力并诱导最高滴度IgG抗体的RBD片段之一。此外，S377-588-Fc在小鼠中引起比所有其他RBD片段更高滴度的中和抗体，并且在免疫的兔中也引起高滴度的中和抗体。结构分析表明，S377-588-Fc含有稳定折叠的RBD结构、完整的受体结合位点和主要的中和表位，因此该片段的其他结构引入非中和表位，也可能改变RBD的三级结构。总之，我们的数据表明，包含刺突残基377-588的RBD片段是关键的中和受体结合片段，是开发有效MERS疫苗的理想候选物，并且向该RBD片段添加非中和结构会降低其中和潜力。因此，在病毒疫苗设计中，重要的是鉴定最稳定和中和的病毒RBD片段，同时消除不必要的和非中和的结构，作为“免疫聚焦”的手段。
We express five MERS-CoV RBDs spanning S350-588, 358-588, 367-588, 377-606, and 377-588. S377-588, 367-588 and 358-588 have the highest receptor binding ability than others. S377-588 and 367-588 induced the highest-titer of IgG antibodies in mice. S377-588 elicits highest neutralization in mice and high neutralization in rabbits. S377-588 contains stably folded RBD structure and major neutralizing epitopes. The newly emerged Middle East respiratory syndrome coronavirus (MERS-CoV) is currently spreading among humans, making development of effective MERS vaccines a high priority. A defined receptor-binding domain (RBD) in MERS-CoV spike protein can potentially serve as a subunit vaccine candidate against MERS-CoV infections. To identify an ideal vaccine candidate, we have constructed five different versions of RBD fragments, S350-588-Fc, S358-588-Fc, S367-588-Fc, S367-606-Fc, and S377-588-Fc (their names indicate their residue range in the spike protein and their C-terminal Fc tag), and further investigated their receptor binding affinity, antigenicity, immunogenicity, and neutralizing potential. The results showed that S377-588-Fc is among the RBD fragments that demonstrated the highest DPP4-binding affinity and induced the highest-titer IgG antibodies in mice. In addition, S377-588-Fc elicited higher-titer neutralizing antibodies than all the other RBD fragments in mice, and also induced high-titer neutralizing antibodies in immunized rabbits. Structural analysis suggests that S377-588-Fc contains the stably folded RBD structure, the full receptor-binding site, and major neutralizing epitopes, such that additional structures to this fragment introduce non-neutralizing epitopes and may also alter the tertiary structure of the RBD. Taken together, our data suggest that the RBD fragment encompassing spike residues 377-588 is a critical neutralizing receptor-binding fragment and an ideal candidate for development of effective MERS vaccines, and that adding non-neutralizing structures to this RBD fragment diminishes its neutralizing potential. Therefore, in viral vaccine design, it is important to identify the most stable and neutralizing viral RBD fragment, while eliminating unnecessary and non-neutralizing structures, as a means of “immunofocusing”.
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影响因子：
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