ABSTRACT
The pandemic of COVID-19 caused by SARS-CoV-2 continues to spread around the world. Mutant strains of SARS-CoV-2 are constantly emerging. At present, Omicron variants have become mainstream. In this work, we carried out a systematic and comprehensive analysis of the reported spike protein antibodies, counting the antibodies' epitopes and genotypes. We further comprehensively analyzed the impact of Omicron mutations on antibody epitopes and classified these antibodies according to their binding patterns. We found that the epitopes of one class of antibodies were significantly less affected by Omicron mutations than other classes. Binding and virus neutralization experiments show that such antibodies can effectively inhibit the immune escape of Omicron. Cryo-EM results show that this class of antibodies utilizes a conserved mechanism to neutralize SARS-CoV-2. Our results greatly help us deeply understand the impact of Omicron mutations. At the same time, it also provides guidance and insights for developing Omicron antibodies and vaccines.
Subject(s)
COVID-19ABSTRACT
The pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents a global public health threat. Most research on therapeutics against SARS-CoV-2 focused on the receptor binding domain (RBD) of the Spike (S) protein, whereas the vulnerable epitopes and functional mechanism of non-RBD regions are poorly understood. Here we isolated and characterized monoclonal antibodies (mAbs) derived from convalescent COVID-19 patients. An mAb targeting the N-terminal domain (NTD) of the SARS-CoV-2 S protein, named 4A8, exhibits high neutralization potency against both authentic and pseudotyped SARS-CoV-2, although it does not block the interaction between angiotensin-converting enzyme 2 (ACE2) receptor and S protein. The cryo-EM structure of the SARS-CoV-2 S protein in complex with 4A8 has been determined to an overall resolution of 3.1 Angstrom and local resolution of 3.4 Angstrom for the 4A8-NTD interface, revealing detailed interactions between the NTD and 4A8. Our functional and structural characterizations discover a new vulnerable epitope of the S protein and identify promising neutralizing mAbs as potential clinical therapy for COVID-19.