Patel Anamika, Kumar Sanjeev, Lai Lilin, Chakravarthy Chennareddy, Valanparambil Rajesh, Reddy Elluri Seetharami, Gottimukkala Kamalvishnu, Bajpai Prashant, Raju Dinesh Ravindra, Edara Venkata Viswanadh, Davis-Gardner Meredith E, Linderman Susanne, Dixit Kritika, Sharma Pragati, Mantus Grace, Cheedarla Narayanaiah, Verkerke Hans P, Frank Filipp, Neish Andrew S, Roback John D, Davis Carl W, Wrammert Jens, Ahmed Rafi, Suthar Mehul S, Sharma Amit, Murali-Krishna Kaja, Chandele Anmol, Ortlund Eric A
Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322, USA.
ICGEB-Emory Vaccine Center, International Center for Genetic Engineering and Biotechnology, New Delhi, 110067, India.
bioRxiv. 2022 Oct 24:2022.10.24.513517. doi: 10.1101/2022.10.24.513517.
A detailed understanding of the molecular features of the neutralizing epitopes developed by viral escape mutants is important for predicting and developing vaccines or therapeutic antibodies against continuously emerging SARS-CoV-2 variants. Here, we report three human monoclonal antibodies (mAbs) generated from COVID-19 recovered individuals during first wave of pandemic in India. These mAbs had publicly shared near germline gene usage and potently neutralized Alpha and Delta, but poorly neutralized Beta and completely failed to neutralize Omicron BA.1 SARS-CoV-2 variants. Structural analysis of these three mAbs in complex with trimeric spike protein showed that all three mAbs are involved in bivalent spike binding with two mAbs targeting class-1 and one targeting class-4 Receptor Binding Domain (RBD) epitope. Comparison of immunogenetic makeup, structure, and function of these three mAbs with our recently reported class-3 RBD binding mAb that potently neutralized all SARS-CoV-2 variants revealed precise antibody footprint, specific molecular interactions associated with the most potent multi-variant binding / neutralization efficacy. This knowledge has timely significance for understanding how a combination of certain mutations affect the binding or neutralization of an antibody and thus have implications for predicting structural features of emerging SARS-CoV-2 escape variants and to develop vaccines or therapeutic antibodies against these.
深入了解病毒逃逸突变体产生的中和表位的分子特征，对于预测和开发针对不断出现的新型冠状病毒2（SARS-CoV-2）变体的疫苗或治疗性抗体至关重要。在此，我们报告了在印度第一波疫情期间从新冠肺炎康复者中产生的三种人源单克隆抗体（mAb）。这些单克隆抗体具有公开共享的近胚系基因使用情况，能有效中和阿尔法和德尔塔变体，但对贝塔变体的中和效果较差，对奥密克戎BA.1 SARS-CoV-2变体则完全没有中和作用。对这三种单克隆抗体与三聚体刺突蛋白复合物的结构分析表明，所有三种单克隆抗体都参与二价刺突结合，其中两种靶向1类，一种靶向4类受体结合域（RBD）表位。将这三种单克隆抗体的免疫遗传组成、结构和功能与我们最近报道的能有效中和所有SARS-CoV-2变体的3类RBD结合单克隆抗体进行比较，揭示了精确的抗体足迹，以及与最有效的多变体结合/中和效力相关的特定分子相互作用。这些知识对于理解某些突变的组合如何影响抗体的结合或中和作用具有及时的意义，因此对于预测新型SARS-CoV-2逃逸变体的结构特征以及开发针对这些变体的疫苗或治疗性抗体具有重要意义。
