预测和减轻对COVID-19疫苗和抗体疗法的突变威胁
Prediction and mitigation of mutation threats to COVID-19 vaccines and antibody therapies
摘要：
抗体疗法和疫苗是我们结束肆虐的COVID-19大流行的最后手段之一。然而，基于超过200，000个基因组分离株的突变追踪器发现，它们在刺突（S）蛋白上倾向于超过5，000个突变。必须了解突变如何影响疫苗和抗体的发展。在这项工作中，我们研究了S蛋白突变的机制，频率和比例。此外，我们使用了56个抗体结构，并分析了它们的2D和3D特征。此外，我们预测突变诱导的结合自由能（BFE）的变化为S蛋白和抗体或ACE 2的复合物。通过整合遗传学、生物物理学、深度学习和代数拓扑学，我们揭示了受体结合结构域（RBD）上的462个突变中的大多数将削弱S蛋白与抗体的结合，并破坏抗体疗法和疫苗的有效性和可靠性。确定了31种疫苗逃逸突变体的列表，同时还详细说明了许多其他破坏性突变。我们还发现，大约65%的现有RBD突变，包括最近在英国和南非发现的那些变异，是结合增强突变，导致更具传染性的COVID-19变异。我们发现RBD突变诱导的BFE与抗体和ACE 2结合的极端值增强和减弱之间的差异，表明SARS-CoV-2处于人类感染进化的高级阶段，而人类免疫系统能够产生优化的抗体。这一发现意味着目前的疫苗和抗体药物对新突变的脆弱性。我们的预测通过与S蛋白RBD上超过1,400个深度突变的比较得到了验证。我们的研究结果表明，迫切需要开发新的抗突变疫苗和抗体，并为季节性疫苗接种做好准备。
英文摘要：
Antibody therapeutics and vaccines are among our last resort to end the raging COVID-19 pandemic. They, however, are prone to over 5,000 mutations on the spike (S) protein uncovered by a Mutation Tracker based on over 200,000 genome isolates. It is imperative to understand how mutations would impact vaccines and antibodies in the development. In this work, we study the mechanism, frequency, and ratio of mutations on the S protein. Additionally, we use 56 antibody structures and analyze their 2D and 3D characteristics. Moreover, we predict the mutation-induced binding free energy (BFE) changes for the complexes of S protein and antibodies or ACE2. By integrating genetics, biophysics, deep learning, and algebraic topology, we reveal that most of 462 mutations on the receptor-binding domain (RBD) will weaken the binding of S protein and antibodies and disrupt the efficacy and reliability of antibody therapies and vaccines. A list of 31 vaccine escape mutants is identified, while many other disruptive mutations are detailed as well. We also unveil that about 65\% existing RBD mutations, including those variants recently found in the United Kingdom (UK) and South Africa, are binding-strengthen mutations, resulting in more infectious COVID-19 variants. We discover the disparity between the extreme values of RBD mutation-induced BFE strengthening and weakening of the bindings with antibodies and ACE2, suggesting that SARS-CoV-2 is at an advanced stage of evolution for human infection, while the human immune system is able to produce optimized antibodies. This discovery implies the vulnerability of current vaccines and antibody drugs to new mutations. Our predictions were validated by comparison with more than 1,400 deep mutations on the S protein RBD. Our results show the urgent need to develop new mutation-resistant vaccines and antibodies and to prepare for seasonal vaccinations.
机构、总结、中文摘要均由AI分析而来，可能存在错误，请以论文正文为准。
