Role of specific hemagglutinin amino acids in the immunogenicity and protection of H5N1 influenza virus vaccines

Hoffmann, Erich; Lipatov, A. S.; Webby, Richard J.; Govorkova, Elena A.; Webster, Robert G.

doi:10.1073/pnas.0506416102

Cited by 116 publications

(125 citation statements)

References 21 publications

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“…Anti-HA antibody titers to both H5N1 viruses were observed in surviving mice given the single IM, 2x IM, and single IM + 7d oral regimens (Figure 4). In the single IM + 7d IM treatment group, only anti-HA antibodies against A/Hong Kong/213/03 (H5N1) were detected, confirming previous observations that this heterologous virus better detects anti-HA antibodies (Hoffmann et al, 2005). Mice that underwent the 2x IM + 7d IM treatment had decreased or undetectable anti-HA serum antibodies.…”

Section: Antibody Production After Peramivir Treatmentsupporting

confidence: 73%

Intramuscularly administered neuraminidase inhibitor peramivir is effective against lethal H5N1 influenza virus in mice

Boltz¹,

Ilyushina²,

Arnold³

et al. 2008

Antiviral Research

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The replication efficiency and multi-organ dissemination of some influenza A (H5N1) viruses requires a rapid (re)evaluation of the available antiviral strategies. We assessed five regimens of the neuraminidase (NA) inhibitor peramivir in mice inoculated with H5N1 virus. The regimens differed by: (1) frequency of administration on first day (once vs twice); (2) duration of administration (1 day vs 8 days); (3) route of administration (intramuscular [IM] injection alone or followed by oral administration). In all regimens, BALB/c mice were administered 30 mg/kg peramivir IM one hour after lethal challenge with 5 MLD 50 of A/Vietnam/1203/04 (H5N1) influenza virus. When given only on the day of inoculation, a single IM injection produced a 33% survival rate, which increased to 55% with two injections. Eight-day regimens significantly increased survival; two IM injections followed by 7 daily IM injections was the most effective regimen (100% survival; inhibition of replication in lungs and brain). When this 8-day regimen began at 24 hours after inoculation, 78% of mice survived; 56% survived when treatment began at 48 after hours. Anti-HA antibody titer differed with the peramivir regimen and corresponded to the severity of disease. Overall, our results demonstrate that IM administration of peramivir is effective in promoting the survival of mice infected with systemically replicating H5N1 virus.

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Section: Antibody Production After Peramivir Treatmentsupporting

confidence: 73%

Intramuscularly administered neuraminidase inhibitor peramivir is effective against lethal H5N1 influenza virus in mice

Boltz¹,

Ilyushina²,

Arnold³

et al. 2008

Antiviral Research

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“…It also can expose conserved epitopes hidden by large glycans to elicit an immune response that recognizes HA variants in higher titer. This strategy opens a new direction for vaccine design and, together with other different vaccine strategies (27)(28)(29)(30) and recent discoveries of HAneutralizing antibodies (31)(32)(33)(34)(35)(36), should facilitate the development of vaccines against viruses such as influenza, hepatitis C virus, and HIV.…”

Section: Discussionmentioning

confidence: 99%

Glycans on influenza hemagglutinin affect receptor binding and immune response

Wang

Chen

Tseng

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

282

256

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Recent cases of avian influenza H5N1 and the swine-origin 2009 H1N1 have caused a great concern that a global disaster like the 1918 influenza pandemic may occur again. Viral transmission begins with a critical interaction between hemagglutinin (HA) glycoprotein, which is on the viral coat of influenza, and sialic acid (SA) containing glycans, which are on the host cell surface. To elucidate the role of HA glycosylation in this important interaction, various defined HA glycoforms were prepared, and their binding affinity and specificity were studied by using a synthetic SA microarray. Truncation of the N-glycan structures on HA increased SA binding affinities while decreasing specificity toward disparate SA ligands. The contribution of each monosaccharide and sulfate group within SA ligand structures to HA binding energy was quantitatively dissected. It was found that the sulfate group adds nearly 100-fold (2.04 kcal/mol) in binding energy to fully glycosylated HA, and so does the biantennary glycan to the monoglycosylated HA glycoform. Antibodies raised against HA protein bearing only a single N-linked GlcNAc at each glycosylation site showed better binding affinity and neutralization activity against influenza subtypes than the fully glycosylated HAs elicited. Thus, removal of structurally nonessential glycans on viral surface glycoproteins may be a very effective and general approach for vaccine design against influenza and other human viruses.flu vaccine ͉ glycan binding ͉ glycosylation T he highly pathogenic H5N1 and the 2009 swine-origin influenza A (H1N1) viruses have caused global outbreaks and raised a great concern that further changes in the viruses may occur to bring about a deadly pandemic (1, 2). Important contributions to our understanding of influenza infections have come from the studies on hemagglutinin (HA), a viral coat glycoprotein that binds to specific sialylated glycan receptors in the respiratory tract, allowing the virus to enter the cell (3-6). To cross the species barrier and infect the human population, avian HA must change its receptorbinding preference from a terminally sialylated glycan that contains ␣2,3 (avian)-linked to ␣2,6 (human)-linked sialic acid motifs (7), and this switch could occur through only two mutations, as in the 1918 pandemic (8). Understanding the factors that affect influenza binding to glycan receptors is thus critical for developing methods to control any future crossover influenza strains that have pandemic potential.HA is a homotrimeric transmembrane protein with an ectodomain composed of a globular head and a stem region (3). Both regions carry N-linked oligosaccharides (9), which affect the functional properties of HA (10, 11). Among different subtypes of influenza A viruses, there is extensive variation in the glycosylation sites of the head region, whereas the stem oligosaccharides are more conserved and required for fusion activity (11). Glycans near antigenic peptide epitopes interfere with antibody recognition (12), and glycans near the proteolytic ...

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“…The hemagglutinin inhibition (HI) assay was carried out as previously described (4). Briefly, a serial dilution of the water-extracted IgY antibodies was added to 4 hemagglutinating units of virus in a microtiter plate, the mixture was incubated for 45 min, and 0.5% chicken erythrocytes were added.…”

Section: Methodsmentioning

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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Role of specific hemagglutinin amino acids in the immunogenicity and protection of H5N1 influenza virus vaccines

Cited by 116 publications

References 21 publications

Intramuscularly administered neuraminidase inhibitor peramivir is effective against lethal H5N1 influenza virus in mice

Intramuscularly administered neuraminidase inhibitor peramivir is effective against lethal H5N1 influenza virus in mice

Glycans on influenza hemagglutinin affect receptor binding and immune response

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

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