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The effect of spike mutations on SARS-CoV-2 neutralization.

ABSTRACT: Multiple severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines show protective efficacy, which is most likely mediated by neutralizing antibodies recognizing the viral entry protein, spike. Because new SARS-CoV-2 variants are emerging rapidly, as exemplified by the B.1.1.7, B.1.351, and P.1 lineages, it is critical to understand whether antibody responses induced by infection with the original SARS-CoV-2 virus or current vaccines remain effective. In this study, we evaluate neutralization of a series of mutated spike pseudotypes based on divergence from SARS-CoV and then compare neutralization of the B.1.1.7 spike pseudotype and individual mutations. Spike-specific monoclonal antibody neutralization is reduced dramatically; in contrast, polyclonal antibodies from individuals infected in early 2020 remain active against most mutated spike pseudotypes, but potency is reduced in a minority of samples. This work highlights that changes in SARS-CoV-2 spike can alter neutralization sensitivity and underlines the need for effective real-time monitoring of emerging mutations and their effect on vaccine efficacy.

SUBMITTER: Rees-Spear C

PROVIDER: S-EPMC7936541 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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The effect of spike mutations on SARS-CoV-2 neutralization.

Rees-Spear Chloe C Muir Luke L Griffith Sarah A SA Heaney Judith J Aldon Yoann Y Snitselaar Jonne L JL Thomas Peter P Graham Carl C Seow Jeffrey J Lee Nayung N Rosa Annachiara A Roustan Chloe C Houlihan Catherine F CF Sanders Rogier W RW Gupta Ravindra K RK Cherepanov Peter P Stauss Hans J HJ Nastouli Eleni E Doores Katie J KJ van Gils Marit J MJ McCoy Laura E LE

Cell reports 20210306 12

Multiple severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines show protective efficacy, which is most likely mediated by neutralizing antibodies recognizing the viral entry protein, spike. Because new SARS-CoV-2 variants are emerging rapidly, as exemplified by the B.1.1.7, B.1.351, and P.1 lineages, it is critical to understand whether antibody responses induced by infection with the original SARS-CoV-2 virus or current vaccines remain effective. In this study, we evaluate neutr ...[more]

PMID: 33713594

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Project description:The glycosylation of viral envelope proteins can play important roles in virus biology and immune evasion. The spike (S) glycoprotein of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) includes 22 N-linked glycosylation sequons and 17 O-linked glycosites. We investigated the effect of individual glycosylation sites on SARS-CoV-2 S function in pseudotyped virus infection assays and on sensitivity to monoclonal and polyclonal neutralizing antibodies. In most cases, the removal of individual glycosylation sites decreased the infectiousness of the pseudotyped virus. For glycosylation mutants in the N-terminal domain and the receptor-binding domain (RBD), reduction in pseudotype infectivity was predicted by a commensurate reduction in the level of virion-incorporated S protein and reduced S trafficking to the cell surface. Notably, the presence of a glycan at position N343 within the RBD had diverse effects on neutralization by RBD-specific monoclonal antibodies cloned from convalescent individuals. The N343 glycan reduced the overall sensitivity to polyclonal antibodies in plasma from COVID-19 convalescent individuals, suggesting a role for SARS-CoV-2 S glycosylation in immune evasion. However, vaccination of convalescent individuals produced neutralizing activity that was resilient to the inhibitory effect of the N343 glycan.IMPORTANCEThe attachment of glycans to the spike proteins of viruses during their synthesis and movement through the secretory pathway can affect their properties. This study shows that the glycans attached to the severe acute respiratory syndrome coronavirus-2 spike protein enable its movement to the cell surface and incorporation into virus particles. Certain glycans, including one that is attached to asparagine 343 in the receptor-binding domain of the spike protein, can also affect virus neutralization by antibodies. This glycan can increase or decrease sensitivity to individual antibodies, likely through direct effects on antibody epitopes and modulation of spike conformation. However, the overall effect of the glycan in the context of the polyclonal mixture of antibodies in convalescent serum is to reduce neutralization sensitivity. Overall, this study highlights the complex effects of glycosylation on spike protein function and immune evasion.

Dataset Information

The effect of spike mutations on SARS-CoV-2 neutralization.

Publications

The effect of spike mutations on SARS-CoV-2 neutralization.

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