Structural and functional bases for broad-spectrum neutralization of avian and human influenza A viruses

Sui, Jianhua; Hwang, William C.; Pérez, Sandra; Ge, Wei; Aird, Daniel; Chen, Limei; Santelli, Eugenio; Stec, Boguslaw; Cadwell, Gregory W.; Ali, Maryam; Wan, Hongquan; Murakami, Akikazu; Yammanuru, Anuradha; Han, Thomas; Cox, Nancy J.; Bankston, Laurie A.; Donis, Ruben O.; Liddington, Robert; Marasco, Wayne A.

doi:10.1038/nsmb.1566

Cited by 1,076 publications

(1,319 citation statements)

References 55 publications

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“…It has been reported that there exist highly conserved epitopes in the stem region of the HA molecule that may become a target for a "universal flu vaccine" (3,7,10,14,15). Humanized monoclonal antibodies raised against these conserved epitopes from a single influenza virus strain were shown to provide strong cross-protection against heterologous strains (13).…”

Section: Discussionmentioning

confidence: 99%

Cross-Protection of Chicken Immunoglobulin Y Antibodies against H5N1 and H1N1 Viruses Passively Administered in Mice

Wallach¹,

Webby²,

Islam³

et al. 2011

Clin. Vaccine Immunol.

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Influenza viruses remain a major threat to global health due to their ability to undergo change through antigenic drift and antigenic shift. We postulated that avian IgY antibodies represent a low-cost, effective, and well-tolerated approach that can easily be scaled up to produce enormous quantities of protective antibodies. These IgY antibodies can be administered passively in humans (orally and intranasally) and can be used quickly and safely to help in the fight against an influenza pandemic. In this study, we raised IgY antibodies against H1N1, H3N2, and H5N1 influenza viruses. We demonstrated that, using whole inactivated viruses alone and in combination to immunize hens, we were able to induce a high level of anti-influenza virus IgY in the sera and eggs, which lasted for at least 2 months after two immunizations. Furthermore, we found that by use of in vitro assays to test for the ability of IgY to inhibit hemagglutination (HI test) and virus infectivity (serum neutralization test), IgYs inhibited the homologous as well as in some cases heterologous clades and strains of viruses. Using an in vivo mouse model system, we found that, when administered intranasally 1 h prior to infection, IgY to H5N1 protected 100% of the mice against lethal challenge with H5N1. Of particular interest was the finding that IgY to H5N1 cross-protected against A/Puerto Rico/8/34 (H1N1) both in vitro and in vivo. Based on our results, we conclude that anti-influenza virus IgY can be used to help prevent influenza virus infection.

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Section: Discussionmentioning

confidence: 99%

Cross-Protection of Chicken Immunoglobulin Y Antibodies against H5N1 and H1N1 Viruses Passively Administered in Mice

Wallach¹,

Webby²,

Islam³

et al. 2011

Clin. Vaccine Immunol.

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“…The removal of glycosylation sites on the HA protein can expose conserved epitopes hidden by large glycans to elicit an immune response that recognizes HA variants at a higher titre . Broadly neutralizing HA2 stemspecific monoclonal antibodies with neutralizing activity for H1 clade viruses (Ekiert et al, 2009;Sui et al, 2009) and H3 subtype viruses (Bommakanti et al, 2010;Wang et al, 2010a) have been developed. These studies indicate that epitopes in the stem of HA are conserved and accessible to antibodies.…”

Section: Discussionmentioning

confidence: 99%

Role of stem glycans attached to haemagglutinin in the biological characteristics of H5N1 avian influenza virus

Zhang¹,

Chen²,

Yang³

et al. 2015

Journal of General Virology

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There are three conserved N-linked glycosites, namely, Asn10, Asn23 and Asn286, in the stem region of haemagglutinin (HA) in H5N1 avian influenza viruses (AIVs). To understand the effect of glycosylation in the stem domain of HA on the biological characteristics of H5N1 AIVs, we used site-directed mutagenesis to generate different patterns of stem glycans on the HA of A/Mallard/ Huadong/S/2005. The results indicated that these three N-glycans were dispensable for the generation of replication-competent influenza viruses. However, when N-glycans at Asn10 plus either Asn23 or Asn268 were removed, the cleavability of HA was almost completely blocked, leading to a significant decrease of the growth rates of the mutant viruses in MDCK and CEF cells in comparison with that of the WT virus. Moreover, the mutant viruses lacking these oligosaccharides, particularly the N-glycan at Asn10, revealed a significant decrease in thermostability and pH stability compared with the WT virus. Interestingly, the mutant viruses induced a lower level of neutralizing antibodies against the WT virus, and most of the mutant viruses were more sensitive to neutralizing antibodies than the WT virus. Taken together, these data strongly suggest that the HA stem glycans play a critical role in HA cleavage, replication, thermostability, pH stability, and antigenicity of H5N1 AIVs.

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“…These facts of conservation and sharing of the newly defined Replikins epitopes were not known, and this unawareness and the believed absence of conservation and sharing was the basis of the reason given for decades of not being able to make pan-influenza vaccines which could be used from year to year. However, having reviewed Replikins' technology since 2003 from data provided by the authors, the National Institutes of Health (NIH) first confirmed the influenza epitopes earlier defined by specific Replikins by landing anti-flu antibodies on them (16). This NIH data was simultaneously independently confirmed by studies at Scripps (17).…”

Section: Pan-influenza Vaccinesmentioning

confidence: 58%

Prediction of specific virus outbreaks made from the increased concentration

Bogoch¹,

Bogoch²

2011

Nature Precedings

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Advance warning of pathogen outbreaks has not been possible heretofore. A new class of genomic peptides associated with rapid replication was discovered and named replikins. Software was designed to analyze replikins quantitatively. Replikin concentration changes were measured annually prior to, and "real time" every few days during, the 2009 H1N1 influenza pandemic. Replikins were seen by both linear sequence representation and three-dimensional Xray diffraction, and found to expand on the virus hemagglutinin surface prior to and during the H1N1 pandemic. The possible combination of influenza strains H1N1 (high infectivity) and H5N1 (high lethality) is a matter of global concern (1,2). The risk of a combined H1N1 (high infectivity) -H5N1 (high lethality) outbreak may have increased because first, the Replikin Counts of the two virus strains have risen simultaneously, not seen previously; second, the rise is to the highest levels recorded since 1918 for H1N1, in Mexico (16.7), and since 1957 for H5N1, in Egypt (23.3); and third, clinical outbreaks of each strain are occurring in 2011. These simultaneous conditions may increase the risk that the two virus strains might come into contact with each other more frequently, facilitating transfer of genomic material to form a hybrid.

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Structural and functional bases for broad-spectrum neutralization of avian and human influenza A viruses

Cited by 1,076 publications

References 55 publications

Cross-Protection of Chicken Immunoglobulin Y Antibodies against H5N1 and H1N1 Viruses Passively Administered in Mice

Cross-Protection of Chicken Immunoglobulin Y Antibodies against H5N1 and H1N1 Viruses Passively Administered in Mice

Role of stem glycans attached to haemagglutinin in the biological characteristics of H5N1 avian influenza virus

Prediction of specific virus outbreaks made from the increased concentration

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