Comprehensive characterization of the antibody responses to SARS-CoV-2 Spike protein finds additional vaccine-induced epitopes beyond those for mild infection.
Comprehensive characterization of the antibody responses to SARS-CoV-2 Spike protein finds additional vaccine-induced epitopes beyond those for mild infection.
复制标题
对 SARS-CoV-2 Spike 蛋白的抗体反应的全面表征发现，除了轻度感染的表位之外，还有其他疫苗诱导的表位。
DOI：
10.7554/elife.73490
复制
发表时间：
2022-01-24
期刊：
影响因子：
7.7
通讯作者：
Overbaugh JM
中科院分区：
文献类型：
--
作者：
Garrett ME;Galloway JG;Wolf C;Logue JK;Franko N;Chu HY;Matsen FA 4th;Overbaugh JM
对 COVID-19 大流行的控制将依靠 SARS-CoV-2 疫苗引发的抗体来预防新出现的和未来的变异；为了实现这一目标，需要了解对感染和疫苗接种的体液反应的独特特征，包括不同的疫苗平台。使用 Phage-DMS 分析了具有不同感染和疫苗接种史的个体中 Spike 特异性抗体的表位和逃逸途径。进行主成分分析以识别沿刺突蛋白的抗体结合区域，从而将样品彼此区分开来。在这些表位区域内，我们通过比较含有野生型残基的肽与含有突变残基的肽的抗体结合来确定潜在的逃逸位点。轻度感染的个体具有与融合肽和七肽重复区域内的 S2 亚基表位结合的抗体，而接种疫苗的个体具有另外与 S1 亚基的 N 和 C 末端结构域中的表位结合的抗体，这种模式在因感染而患有严重疾病的个体中也观察到。表位结合似乎在疫苗接种后随着时间的推移而变化，但其他协变量（例如 mRNA 疫苗剂量、mRNA 疫苗类型和年龄）并不影响抗体与这些表位的结合。疫苗接种在个体之间诱导了相对一致的某些表位的逃逸特征，而轻度感染个体的逃逸途径则有更多的变化。在针对融合肽区域的抗体的情况下，融合肽区域是对感染和疫苗接种的常见反应，感染后的逃逸特征不会因后续疫苗接种而改变。 SARS-CoV-2 mRNA 疫苗接种导致与感染后观察到的其他表位结合的发现表明，保护作用可能会因暴露于 Spike 抗原的途径而异。相对于感染诱导的抗体，疫苗诱导的抗体的逃逸途径相对保守，这表明如果出现逃逸变异，它们可能很容易在接种疫苗的个体中被选择。鉴于大多数人将通过疫苗接种而不是感染首先接触 Spike，这项工作对于预测人群水平上免疫逃逸变异的选择具有重要意义。这项工作得到了 NIH 拨款 AI138709 (PI JMO) 和 AI146028 (PI FAM) 的支持。 JMO 获得了研究生教育捐赠主席 (FHCRC) 的支持。 FAM 的研究部分得到了霍华德休斯医学研究所和西蒙斯基金会的教职学者资助。 Fred Hutch 的科学计算基础设施由 ORIP 拨款 S10OD028685 资助。当 SARS-CoV-2（导致 COVID-19 的病毒）感染我们的身体时，我们的免疫系统会产生反应，产生称为抗体的小分子，这些小分子粘附在病毒的刺突蛋白部分上。人们认为疫苗的作用是通过触发类似抗体的产生而不会引起疾病。一些最有效的抗 SARS-CoV-2 抗体与刺突蛋白的特定区域（称为“受体结合域”或 RBD）结合。当 SARS-CoV-2 进化时，它会给我们的免疫系统带来挑战：突变（即病毒遗传密码的变化）可以改变其刺突蛋白的形状，这意味着现有的抗体可能不再有效地与其结合。这降低了过去感染或疫苗接种所提供的保护，从而使应对这一流行病变得更加困难。目前尚不清楚病毒遗传密码的哪些突变会影响抗体结合，特别是与 RBD 之外的部分的结合。更复杂的是，人们针对轻度感染、重度感染和疫苗接种产生的抗体虽然有些重叠，但也表现出一些差异。研究这些差异可能有助于最大限度地减少病毒“逃避”抗体反应的突变的出现。噬菌体展示库是一种实验室技术，其中噬菌体（感染细菌的病毒）被用作编码特定蛋白质的 DNA 片段的“存储库”。然后噬菌体可以产生蛋白质（或其片段），如果蛋白质片段与目标结合，就可以很容易地检测到。加勒特，加洛韦等人。利用这项技术来研究 SARS-CoV-2 刺突蛋白的不同部分如何与抗体结合。他们制作了一个噬菌体文库，其中每个噬菌体都编码具有不同突变的刺突蛋白的一部分，然后将该蛋白的不同版本暴露于来自先前经历过感染、接种疫苗或两者的人的抗体。实验表明，严重感染期间或接种疫苗后产生的抗体与刺突蛋白的相似部分结合，而经历过轻度感染的人的抗体则针对较少的区域。加勒特，加洛韦等人。还发现影响疫苗接种后产生的抗体结合的突变比干扰感染期间产生的抗体的突变更加一致。虽然这些结果表明哪些突变最有可能帮助病毒逃避现有抗体，但这并不意味着病毒一定会朝这个方向进化。事实上，有些突变对于病毒来说可能是不可能获得的，因为它们会干扰病毒的传播能力。进一步的研究可能集中于揭示 Garrett、Galloway 等人检测到的哪些突变。最有可能发生的情况，以指导疫苗朝这个方向开发。为了解决这个问题，Garrett、Galloway 等人。使用网络工具使其他科学家和公众可以访问这些数据。
Control of the COVID-19 pandemic will rely on SARS-CoV-2 vaccine-elicited antibodies to protect against emerging and future variants; an understanding of the unique features of the humoral responses to infection and vaccination, including different vaccine platforms, is needed to achieve this goal. The epitopes and pathways of escape for Spike-specific antibodies in individuals with diverse infection and vaccination history were profiled using Phage-DMS. Principal component analysis was performed to identify regions of antibody binding along the Spike protein that differentiate the samples from one another. Within these epitope regions, we determined potential sites of escape by comparing antibody binding of peptides containing wild-type residues versus peptides containing a mutant residue. Individuals with mild infection had antibodies that bound to epitopes in the S2 subunit within the fusion peptide and heptad-repeat regions, whereas vaccinated individuals had antibodies that additionally bound to epitopes in the N- and C-terminal domains of the S1 subunit, a pattern that was also observed in individuals with severe disease due to infection. Epitope binding appeared to change over time after vaccination, but other covariates such as mRNA vaccine dose, mRNA vaccine type, and age did not affect antibody binding to these epitopes. Vaccination induced a relatively uniform escape profile across individuals for some epitopes, whereas there was much more variation in escape pathways in mildly infected individuals. In the case of antibodies targeting the fusion peptide region, which was a common response to both infection and vaccination, the escape profile after infection was not altered by subsequent vaccination. The finding that SARS-CoV-2 mRNA vaccination resulted in binding to additional epitopes beyond what was seen after infection suggests that protection could vary depending on the route of exposure to Spike antigen. The relatively conserved escape pathways to vaccine-induced antibodies relative to infection-induced antibodies suggests that if escape variants emerge they may be readily selected for across vaccinated individuals. Given that the majority of people will be first exposed to Spike via vaccination and not infection, this work has implications for predicting the selection of immune escape variants at a population level. This work was supported by NIH grants AI138709 (PI JMO) and AI146028 (PI FAM). JMO received support as the Endowed Chair for Graduate Education (FHCRC). The research of FAM was supported in part by a Faculty Scholar grant from the Howard Hughes Medical Institute and the Simons Foundation. Scientific Computing Infrastructure at Fred Hutch was funded by ORIP grant S10OD028685. When SARS-CoV-2 – the virus that causes COVID-19 – infects our bodies, our immune system reacts by producing small molecules called antibodies that stick to a part of the virus called the spike protein. Vaccines are thought to work by triggering the production of similar antibodies without causing disease. Some of the most effective antibodies against SARS-CoV-2 bind a specific area of the spike protein called the ‘receptor binding domain’ or RBD. When SARS-CoV-2 evolves it creates a challenge for our immune system: mutations, which are changes in the virus’s genetic code, can alter the shape of its spike protein, meaning that existing antibodies may no longer bind to it as effectively. This lowers the protection offered by past infection or vaccination, which makes it harder to tackle the pandemic. As it stands, it is not clear which mutations to the virus’s genetic code can affect antibody binding, especially to portions outside the RBD. To complicate things further, the antibodies people produce in response to mild infection, severe infection, and vaccination, while somewhat overlapping, exhibit some differences. Studying these differences could help minimize emergence of mutations that allow the virus to ‘escape’ the antibody response. A phage display library is a laboratory technique in which phages (viruses that infect bacteria) are used as a ‘repository’ for DNA fragments that code for a specific protein. The phages can then produce the protein (or fragments of it), and if the protein fragments bind to a target, it can be easily detected. Garrett, Galloway et al. exploited this technique to study how different portions of the SARS-CoV-2 spike protein were bound by antibodies. They made a phage library in which each phage encoded a portion of the spike protein with different mutations, and then exposed the different versions of the protein to antibodies from people who had experienced prior infection, vaccination, or both. The experiment showed that antibodies produced during severe infection or after vaccination bound to similar parts of the spike protein, while antibodies from people who had experienced mild infection targeted fewer areas. Garrett, Galloway et al. also found that mutations that affected the binding of antibodies produced after vaccination were more consistent than mutations that interfered with antibodies produced during infection. While these results show which mutations are most likely to help the virus escape existing antibodies, this does not mean that the virus will necessarily evolve in that direction. Indeed, some of the mutations may be impossible for the virus to acquire because they interfere with the virus’s ability to spread. Further studies could focus on revealing which of the mutations detected by Garrett, Galloway et al. are most likely to occur, to guide vaccine development in that direction. To help with this, Garrett, Galloway et al. have made the data accessible to other scientists and the public using a web tool.