Unmasking Stem-Specific Neutralizing Epitopes by Abolishing N-Linked Glycosylation Sites of Influenza Virus Hemagglutinin Proteins for Vaccine Design

Liu, Wen-Chun; Jan, Jia-Tsrong; Huang, Yun-Ju; Chen, Ting‐Hsuan; Wu, Suh-Chin

doi:10.1128/jvi.00880-16

Cited by 40 publications

(41 citation statements)

References 39 publications

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“…While PNGase F would release N-linked glycan moieties between GlcNAc and ASN residues within a glycoprotein. It should be noted that glycosylation in insect cells is featured as terminal mannose glycans, unlike complex sialylated glycans in mammalian cells, and glycosylation is known to correlate the immunogenicity and broad-coverage protection of a glycoprotein immunogen 15, 16 . After the treatment of either Endo H or PNGase F, RBD showed no discernible decrease of molecular weight in SDS-PAGE/anti-His WB, S1 and S2 both demonstrated nearly ∼10 kDa decrease, and the intact S exhibited substantial shrinkage in molecular weight of about ∼20 kDa decrease (Fig.…”

Section: Resultsmentioning

confidence: 99%

Characterization of the SARS-CoV-2 Spike in an Early Prefusion Conformation

Zheng

et al. 2020

Preprint

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23Pandemic coronavirus disease 2019 is caused by the emerging severe 24 acute respiratory syndrome coronavirus 2 (SARS-CoV-2), for which there are no 25 efficacious vaccines or therapeutics that are urgently needed. We expressed three 26 versions of spike (S) proteins-receptor binding domain (RBD), S1 subunit and S 27 ectodomain-in insect cells. RBD appears monomer in solutions, whereas S1 and S 28 associate into homotrimer with substantial glycosylation. The three proteins confer 29 excellent antigenicity with six convalescent COVID-19 patient sera. Cryo-electron 30 microscopy (cryo-EM) analyses indicate that the SARS-CoV-2 S trimer dominate in a 31 unique conformation distinguished from the classic prefusion conformation of 32 coronaviruses by the upper S1 region at lower position ~15 Å proximal to viral 33 membrane. Such conformation is proposed as an early prefusion state for the SARS-34 CoV-2 spike that may broaden the knowledge of coronavirus and facilitate vaccine 35 development.36

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Section: Resultsmentioning

confidence: 99%

Characterization of the SARS-CoV-2 Spike in an Early Prefusion Conformation

Zheng

et al. 2020

Preprint

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“…A number of studies engineered glycans to expose the hidden conserved epitopes in the HA domain. For instance, one article reported that modifying glycosylation sites in the HA stem region leads to unmasked sites by N-glycans that elicit effective broadly neutralizing antibodies [80]. Such studies confirmed the potential role of engineering in changing the immunogenicity of antigens and exposing conserved sites, which are the key to induce broadly neutralizing antibodies [76,81,82].…”

Section: Recent Advances In Anti-ha Antibodiesmentioning

confidence: 88%

Recent advances in “universal” influenza virus antibodies: the rise of a hidden trimeric interface in hemagglutinin globular head

Wang

et al. 2020

Front. Med.

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Influenza causes seasonal outbreaks yearly and unpredictable pandemics with high morbidity and mortality rates. Despite significant efforts to address influenza, it remains a major threat to human public health. This issue is partially due to the lack of antiviral drugs with potent antiviral activity and broad reactivity against all influenza virus strains and the rapid emergence of drug-resistant variants. Moreover, designing a universal influenza vaccine that is sufficiently immunogenic to induce universal antibodies is difficult. Some novel epitopes hidden in the hemagglutinin (HA) trimeric interface have been discovered recently, and a number of antibodies targeting these epitopes have been found to be capable of neutralizing a broad range of influenza isolates. These findings may have important implications for the development of universal influenza vaccines and antiviral drugs. In this review, we focused on the antibodies targeting these newly discovered epitopes in the HA domain of the influenza virus to promote the development of universal anti-influenza antibodies or vaccines and extend the discovery to other viruses with similar conformational changes in envelope proteins.

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“…For example, through identification of conserved glycosites in the stem region of the influenza strain H5, novel vaccine candidates were created. By mutation of certain conserved glycosites, it was possible to make a vaccine resulting in a refocused B‐cell response with improved neutralization of homologous, heterologous, and heterosubtypic viruses . While protection against challenge with lethal homologous virus was substantially improved, high mortality was still observed when challenged with a virus of a different subtype, showing that further vaccine optimization is needed .…”

Section: Practical Implications Of Glycosite Discovery In Virologymentioning

confidence: 99%

“…By mutation of certain conserved glycosites, it was possible to make a vaccine resulting in a refocused B‐cell response with improved neutralization of homologous, heterologous, and heterosubtypic viruses . While protection against challenge with lethal homologous virus was substantially improved, high mortality was still observed when challenged with a virus of a different subtype, showing that further vaccine optimization is needed . Modulating glycan density on immunogens has been one of the approaches utilized in vaccine design .…”

Section: Practical Implications Of Glycosite Discovery In Virologymentioning

confidence: 99%

Viral glycoproteomes: technologies for characterization and outlook for vaccine design

et al. 2018

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It has long been known that surface proteins of most enveloped viruses are covered with glycans. It has furthermore been demonstrated that glycosylation is essential for propagation and immune evasion for many viruses. The recent development of high-resolution mass spectrometry techniques has enabled identification not only of the precise structures but also the positions of such post-translational modifications on viruses, revealing substantial differences in extent of glycosylation and glycan maturation for different classes of viruses. In-depth characterization of glycosylation and other post-translational modifications of viral envelope glycoproteins is essential for rational design of vaccines and antivirals. In this Review, we provide an overview of techniques used to address viral glycosylation and summarize information on glycosylation of enveloped viruses representing ongoing public health challenges. Furthermore, we discuss how knowledge on glycosylation can be translated to means to prevent and combat viral infections.

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Unmasking Stem-Specific Neutralizing Epitopes by Abolishing N-Linked Glycosylation Sites of Influenza Virus Hemagglutinin Proteins for Vaccine Design

Cited by 40 publications

References 39 publications

Characterization of the SARS-CoV-2 Spike in an Early Prefusion Conformation

Characterization of the SARS-CoV-2 Spike in an Early Prefusion Conformation

Recent advances in “universal” influenza virus antibodies: the rise of a hidden trimeric interface in hemagglutinin globular head

Viral glycoproteomes: technologies for characterization and outlook for vaccine design

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