Miller Nathaniel L, Clark Thomas, Raman Rahul, Sasisekharan Ram
Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
bioRxiv. 2021 Dec 10:2021.12.06.471499. doi: 10.1101/2021.12.06.471499.
The SARS-COV2 Omicron variant has sparked global concern due to the possibility of enhanced transmissibility and escape from vaccines and therapeutics. In this study, we describe the mutational landscape of the Omicron variant using amino acid interaction (AAI) networks. AAI network analysis is particularly well suited for interrogating the impact of constellations of mutations as occur on Omicron that may function in an epistatic manner. Our analyses suggest that as compared to previous variants of concern, the Omicron variant has increased antibody escape due to mutations in class 3 and 4 antibody epitopes as well as increased escape due to accumulated mutations in class 1 antibody epitopes. We note certain RBD mutations that might further enhance Omicron's escape, and in particular advise careful surveillance of two subclades bearing R346S/K mutations with relevance for certain therapeutic antibodies. Further, AAI network analysis suggests that the function of certain therapeutic monoclonal antibodies may be disrupted by Omicron mutations as a result of the cumulative indirect perturbations to the epitope surface properties, despite point-mutation analyses suggesting these antibodies are tolerant of the set of Omicron mutations in isolation. Finally, for several Omicron mutations that do not appear to contribute meaningfully to antibody escape, we find evidence for a plausible role in enhanced transmissibility via disruption of RBD-down conformational stability at the RBD-RBD interface.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）奥密克戎变异株因其可能增强的传播性以及对疫苗和治疗方法的逃逸能力而引发了全球关注。在本研究中，我们使用氨基酸相互作用（AAI）网络描述了奥密克戎变异株的突变图谱。AAI网络分析特别适合于探究奥密克戎变异株上可能以上位性方式起作用的突变组合的影响。我们的分析表明，与先前令人关注的变异株相比，奥密克戎变异株由于3类和4类抗体表位的突变而增加了抗体逃逸，同时也由于1类抗体表位中积累的突变而增加了逃逸。我们注意到某些受体结合域（RBD）突变可能会进一步增强奥密克戎的逃逸能力，尤其建议对携带R346S/K突变且与某些治疗性抗体相关的两个亚分支进行密切监测。此外，AAI网络分析表明，尽管点突变分析表明某些治疗性单克隆抗体单独对奥密克戎变异株的一组突变具有耐受性，但由于表位表面性质的累积间接扰动，奥密克戎变异株的突变可能会破坏这些治疗性单克隆抗体的功能。最后，对于一些似乎对抗体逃逸没有显著贡献的奥密克戎变异株突变，我们发现有证据表明它们可能通过破坏RBD-RBD界面处RBD向下的构象稳定性在增强传播性方面发挥合理作用。
