Glycan Masking of Epitopes in the NTD and RBD of the Spike Protein Elicits Broadly Neutralizing Antibodies Against SARS-CoV-2 Variants

Lin, Wei-Shuo; Chen, I-Chen; Chen, Hui-Chen; Lee, Yi-Chien; Wu, Suh-Chin

doi:10.3389/fimmu.2021.795741

Cited by 18 publications

(17 citation statements)

References 39 publications

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“…Similarly, the design of next-generation vaccines against COVID-19 may need to focus on minimizing the negative impact of antigenic imprinting, however, further investigation will be needed to understand the role of the antigenic imprinting during infection. While several promising candidates of broadly protective SARS-CoV-2 vaccines have been developed [ 34 , 35 ], it will be important to assess whether their continued effectiveness is influenced by prior immune history.…”

Section: Discussionmentioning

confidence: 99%

Neutralizing Antibody Response to Sarbecovirus Is Delayed in Sequential Heterologous Immunization

Teo

et al. 2022

Viruses

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Antigenic imprinting, which describes the bias of the antibody response due to previous immune history, can influence vaccine effectiveness. While this phenomenon has been reported for viruses such as influenza, there is little understanding of how prior immune history affects the antibody response to SARS-CoV-2. This study provides evidence for antigenic imprinting through immunization with two Sarbecoviruses, the subgenus that includes SARS-CoV-2. Mice were immunized subsequently with two antigenically distinct Sarbecovirus strains, namely SARS-CoV-1 and SARS-CoV-2. We found that sequential heterologous immunization induced cross-reactive binding antibodies for both viruses and delayed the emergence of neutralizing antibody responses against the booster strain. Our results provide fundamental knowledge about the immune response to Sarbecovirus and important insights into the development of pan-sarbecovirus vaccines and guiding therapeutic interventions.

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Section: Discussionmentioning

confidence: 99%

Neutralizing Antibody Response to Sarbecovirus Is Delayed in Sequential Heterologous Immunization

Teo

et al. 2022

Viruses

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“…The emergence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has led to the coronavirus disease 2019 (COVID- 19) pandemic (1,2). As the major antigen of SARS-CoV-2, spike (S) glycoprotein plays a critical role in facilitating virus entry (3,4).…”

Section: Introductionmentioning

confidence: 99%

Probing the biophysical constraints of SARS-CoV-2 spike N-terminal domain using deep mutational scanning

et al. 2022

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Increasing the expression level of the SARS-CoV-2 spike (S) protein has been critical for COVID-19 vaccine development. While previous efforts largely focused on engineering the receptor-binding domain (RBD) and the S2 subunit, the amino-terminal domain (NTD) has been long overlooked because of the limited understanding of its biophysical constraints. In this study, the effects of thousands of NTD single mutations on S protein expression were quantified by deep mutational scanning. Our results revealed that in terms of S protein expression, the mutational tolerability of NTD residues was inversely correlated with their proximity to the RBD and S2. We also identified NTD mutations at the interdomain interface that increased S protein expression without altering its antigenicity. Overall, this study not only advances the understanding of the biophysical constraints of the NTD but also provides invaluable insights into S-based immunogen design.

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“…The monosaccharide N-acetylglucosamine (GlcNAc) at the HA glycosite was attributed to better neutralization and cross-protection against H1, H3, H5, and H7 strains and subtypes, and overall vaccine efficacy was increased when the recombinant HA antigen-based vaccine was combined with a glycolipid adjuvant (Liao et al, 2020). Interestingly, N-linked glycans on the H5 antigen globular head domain and glycanunmasking at the stem region elicit broad neutralizing antibodies to cross-protect against various H5N1 clades of virus infection (Chen et al, 2021); while the mechanism of introducing additional Nglycosylation sites was recently also applied to the modification of SARS-CoV-2 S glycoprotein (Galili, 2020;Lin et al, 2021). Glycans found on the SARS-CoV-2 S trimer (Watanabe et al, 2020) revealed few, but invariant interactions with human neutralizing antibodies to SARS-CoV-2 WT, the Alpha, Delta, Lambda, and Omicron variants (Wang et al, 2022), from which many were isolated, investigated during the current pandemics (Robbiani et al, 2020;Barnes et al, 2020a) and classified according to their binding capacities for epitopes on S trimer.…”

Section: Structural Features For Targeting Glycoproteinsmentioning

confidence: 99%

Engineering recombinantly expressed lectin-based antiviral agents

Maier

2022

Front. Cell. Infect. Microbiol.

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Cyanovirin-N (CV-N), a lectin from Nostoc ellipsosporum was found an infusion inhibitory protein for human immunodeficiency virus (HIV)-1. A tandem-repeat of the engineered domain-swapped dimer bound specific sites at hemagglutinin (HA), Ebola and HIV spike glycoproteins as well as dimannosylated HA peptide, N-acetyl-D-glucosamine and high-mannose containing oligosaccharides. Among these, CV-N bound the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) spike protein at a dissociation constant (KD) of 18.6 µM (and KD=260 µM to RBD), which was low-affinity carbohydrate-binding as compared with the recognition of the other viral spikes. Binding of dimannosylated peptide to homo-dimeric CVN2 and variants of CVN2 that were pairing Glu-Arg residues sterically located close to its high-affinity carbohydrate binding sites, was measured using surface plasmon resonance (SPR) and isothermal titration calorimetry (ITC). Binding affinity increased with polar interactions, when the mutated residues were used to substitute a single, or two disulfide bonds, in CVN2. Site-specific N-linked glycans on spikes were mediating the infection with influenza virus by broadly neutralizing antibodies to HA and lectin binding to HA was further investigated via modes of saturation transfer difference (STD)-NMR. Our findings showed that stoichiometry and the lectin’s binding affinity were revealed by an interaction of CVN2 with dimannose units and either the high- or low-affinity binding site. To understand how these binding mechanisms add to viral membrane fusion we compare our tested HA-derived peptides in affinity with SARS-CoV-2 glycoprotein and review lectins and their mechanisms of binding to enveloped viruses for a potential use to simulate neutralization ability.

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Glycan Masking of Epitopes in the NTD and RBD of the Spike Protein Elicits Broadly Neutralizing Antibodies Against SARS-CoV-2 Variants

Cited by 18 publications

References 39 publications

Neutralizing Antibody Response to Sarbecovirus Is Delayed in Sequential Heterologous Immunization

Neutralizing Antibody Response to Sarbecovirus Is Delayed in Sequential Heterologous Immunization

Probing the biophysical constraints of SARS-CoV-2 spike N-terminal domain using deep mutational scanning

Engineering recombinantly expressed lectin-based antiviral agents

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