Escape from neutralizing antibodies by SARS-CoV-2 spike protein variants.
Escape from neutralizing antibodies by SARS-CoV-2 spike protein variants.
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DOI：
10.7554/elife.61312
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发表时间：
2020-10-28
期刊：
影响因子：
7.7
通讯作者：
Bieniasz PD
中科院分区：
文献类型：
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作者：
Weisblum Y;Schmidt F;Zhang F;DaSilva J;Poston D;Lorenzi JC;Muecksch F;Rutkowska M;Hoffmann HH;Michailidis E;Gaebler C;Agudelo M;Cho A;Wang Z;Gazumyan A;Cipolla M;Luchsinger L;Hillyer CD;Caskey M;Robbiani DF;Rice CM;Nussenzweig MC;Hatziioannou T;Bieniasz PD
先前感染或接种疫苗引发的中和抗体可能是未来保护个人和人群免受SARS-CoV-2感染的关键。此外，被动注射抗体是最有希望的治疗和预防SARS-CoV-2的药物之一。然而，SARS-CoV-2将在多大程度上适应逃避中和抗体尚不清楚。利用重组VSV/SARS-CoV-2嵌合报告病毒，我们发现可以很容易地选择具有功能性的SARS-CoV-2 S蛋白变异体，其受体结合域和N-末端结构域发生突变，从而对单抗或恢复期血浆产生抵抗力。值得注意的是，SARS-CoV-2 S变种能抵抗通常激发的中和抗体，目前在SARS-CoV-2循环人群中出现频率很低。最后，通过使用针对不同中和表位的抗体组合，可以缓解抗体抗药性SARS-CoV-2变种的出现，这种变种可能限制单抗的治疗用途。导致新冠肺炎疾病的新型冠状病毒SARS-CoV-2已经对世界范围内的人类健康产生了严重影响。在2020年初，这种病毒几乎是未知的。自那以后，紧张的研究工作导致了对冠状病毒基因组的测序，确定了其蛋白质的结构，并创造了一系列工具来搜索有效的疫苗和疗法。抗体是人体产生的免疫分子，针对病毒蛋白的特定片段，可以中和病毒颗粒，并触发免疫系统杀死感染病毒的细胞。目前正在开发几项利用抗体的技术，包括疫苗、先前感染患者的血浆、制造抗体等。SARS-CoV-2表面的刺突蛋白被认为是主要的抗体靶标，因为它们可以接触到，并在允许病毒附着和感染宿主细胞方面发挥重要作用。抗体与刺突蛋白结合，一些抗体可以阻止病毒感染新细胞的能力。但一些病毒，如艾滋病毒和流感，能够通过突变其等同的尖峰蛋白来逃避抗体。目前尚不清楚SARS-CoV-2是否能够以同样的方式有效地进化来逃避抗体。Weisblum，Schmidt等人。使用一种模拟人类人口自然感染的人工系统解决了这个问题。在实验室中培养的人类细胞被一种混合病毒感染，这种混合病毒是通过修改一种无害的动物病毒而产生的，这种病毒含有SARS-CoV-2刺突蛋白，并用人造抗体或康复的新冠肺炎患者血液中存在的抗体进行治疗。在这种情况下，只有变异的病毒能够逃脱抗体才能存活。出现的几个病毒突变株进化出了尖峰蛋白，其中抗体靶向的片段发生了变化，使得这些突变病毒保持在未被检测到的状态。对从患者样本中分离的50,000多个现实生活中的SARS-CoV-2基因组的分析进一步表明，这些病毒突变中的大多数已经在传播，尽管在受感染的人群中水平非常低。这些结果表明，SARS-CoV-2可以通过突变其尖峰蛋白来逃避抗体，而且这些突变已经存在于一些在人类群体中传播的病毒突变中。这表明，任何大规模部署的疫苗都应该被设计成针对尖峰蛋白上的多个靶区激活尽可能最强的免疫反应。此外，结合使用两种抗体的基于抗体的疗法应该防止对抗体产生抗药性的病毒的上升，并保持疫苗和疗法的长期有效性。
Neutralizing antibodies elicited by prior infection or vaccination are likely to be key for future protection of individuals and populations against SARS-CoV-2. Moreover, passively administered antibodies are among the most promising therapeutic and prophylactic anti-SARS-CoV-2 agents. However, the degree to which SARS-CoV-2 will adapt to evade neutralizing antibodies is unclear. Using a recombinant chimeric VSV/SARS-CoV-2 reporter virus, we show that functional SARS-CoV-2 S protein variants with mutations in the receptor-binding domain (RBD) and N-terminal domain that confer resistance to monoclonal antibodies or convalescent plasma can be readily selected. Notably, SARS-CoV-2 S variants that resist commonly elicited neutralizing antibodies are now present at low frequencies in circulating SARS-CoV-2 populations. Finally, the emergence of antibody-resistant SARS-CoV-2 variants that might limit the therapeutic usefulness of monoclonal antibodies can be mitigated by the use of antibody combinations that target distinct neutralizing epitopes. The new coronavirus, SARS-CoV-2, which causes the disease COVID-19, has had a serious worldwide impact on human health. The virus was virtually unknown at the beginning of 2020. Since then, intense research efforts have resulted in sequencing the coronavirus genome, identifying the structures of its proteins, and creating a wide range of tools to search for effective vaccines and therapies. Antibodies, which are immune molecules produced by the body that target specific segments of viral proteins can neutralize virus particles and trigger the immune system to kill cells infected with the virus. Several technologies are currently under development to exploit antibodies, including vaccines, blood plasma from patients who were previously infected, manufactured antibodies and more. The spike proteins on the surface of SARS-CoV-2 are considered to be prime antibody targets as they are accessible and have an essential role in allowing the virus to attach to and infect host cells. Antibodies bind to spike proteins and some can block the virus’ ability to infect new cells. But some viruses, such as HIV and influenza, are able to mutate their equivalent of the spike protein to evade antibodies. It is unknown whether SARS-CoV-2 is able to efficiently evolve to evade antibodies in the same way. Weisblum, Schmidt et al. addressed this question using an artificial system that mimics natural infection in human populations. Human cells grown in the laboratory were infected with a hybrid virus created by modifying an innocuous animal virus to contain the SARS-CoV-2 spike protein, and treated with either manufactured antibodies or antibodies present in the blood of recovered COVID-19 patients. In this situation, only viruses that had mutated in a way that allowed them to escape the antibodies were able to survive. Several of the virus mutants that emerged had evolved spike proteins in which the segments targeted by the antibodies had changed, allowing these mutant viruses to remain undetected. An analysis of more than 50,000 real-life SARS-CoV-2 genomes isolated from patient samples further showed that most of these virus mutations were already circulating, albeit at very low levels in the infected human populations. These results show that SARS-CoV-2 can mutate its spike proteins to evade antibodies, and that these mutations are already present in some virus mutants circulating in the human population. This suggests that any vaccines that are deployed on a large scale should be designed to activate the strongest possible immune response against more than one target region on the spike protein. Additionally, antibody-based therapies that use two antibodies in combination should prevent the rise of viruses that are resistant to the antibodies and maintain the long-term effectiveness of vaccines and therapies.