SARS-CoV-2 variants of concern: spike protein mutational analysis and epitope for broad neutralization

Mutations in the spike glycoproteins of SARS-CoV-2 variants of concern have independently been shown to enhance aspects of spike protein fitness. Here, we describe an antibody fragment (V H ab6) that neutralizes all major variants including the recently emerged BA.1 and BA.2 Omicron subvariants, wit...

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Published in:Nature communications 2022-08, Vol.13 (1), p.4696-4696, Article 4696
Main Authors: Mannar, Dhiraj, Saville, James W., Sun, Zehua, Zhu, Xing, Marti, Michelle M., Srivastava, Shanti S., Berezuk, Alison M., Zhou, Steven, Tuttle, Katharine S., Sobolewski, Michele D., Kim, Andrew, Treat, Benjamin R., Da Silva Castanha, Priscila Mayrelle, Jacobs, Jana L., Barratt-Boyes, Simon M., Mellors, John W., Dimitrov, Dimiter S., Li, Wei, Subramaniam, Sriram
Format: Article
Language:English
Subjects:
101/1
101/28
631/45
631/535
Antibodies
Antigens
Comparative analysis
Epitopes
Glycoproteins
Humanities and Social Sciences
multidisciplinary
Mutation
Neutralization
Protein structure
Proteins
Science
Science (multidisciplinary)
Severe acute respiratory syndrome
Severe acute respiratory syndrome coronavirus 2
Spike protein
Structure-function relationships
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Summary:Mutations in the spike glycoproteins of SARS-CoV-2 variants of concern have independently been shown to enhance aspects of spike protein fitness. Here, we describe an antibody fragment (V H ab6) that neutralizes all major variants including the recently emerged BA.1 and BA.2 Omicron subvariants, with a unique mode of binding revealed by cryo-EM studies. Further, we provide a comparative analysis of the mutational effects within previously emerged variant spikes and identify the structural role of mutations within the NTD and RBD in evading antibody neutralization. Our analysis shows that the highly mutated Gamma N-terminal domain exhibits considerable structural rearrangements, partially explaining its decreased neutralization by convalescent sera. Our results provide mechanistic insights into the structural, functional, and antigenic consequences of SARS-CoV-2 spike mutations and highlight a spike protein vulnerability that may be exploited to achieve broad protection against circulating variants. SARS-CoV-2 variants have accumulated multiple defining mutations within their spike glycoproteins. Here, the authors report a structural basis for broad neutralization of several variants by a heavy chain antibody fragment and provide a mutational analysis focusing on antibody evasion, receptor engagement, and spike protein structure.
ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-022-32262-8