Guiding the Immune Response against Influenza Virus Hemagglutinin toward the Conserved Stalk Domain by Hyperglycosylation of the Globular Head Domain

Eggink, Dirk; Goff, Peter H.; Palese, Peter

doi:10.1128/jvi.02608-13

Cited by 162 publications

(149 citation statements)

References 37 publications

Supporting

Mentioning

145

Contrasting

Order By: Relevance

“…Also, the presence of the immune-dominant globular head region may dilute the outcomes of the stem glycan removal strategy in terms of heterosubtypic protection. Therefore, this vaccine design still needs further optimization to include other strategies such as the combination with globular head glycan masking, as we and others previously reported (19)(20)(21). All of these results can provide useful information for developing more effective influenza vaccines.…”

Section: Discussionmentioning

confidence: 73%

“…The binding sites in the HA2 stem for CR6261 and Fl6v3 are not completely overlapped (25), for the interaction of FI6v3 with the hydrophobic groove on HA is mediated by long HCDR3 (heavy-chain constant domain region 3) and LCDR1 (light-chain constant domain region 1), whereas CR6261 interacted with all of three HCDRs (CDR1 to CDR3). Both antibodies (FI6v3 and CR6261) make contacts with Trp 21 , mainly through a phenylalanine side chain: Phe 100D on FI6v3 and Phe 54 on CR6261 (25). Both CR6261 and FI6v3 bNAbs demonstrated complete inhibition in the cell fusion assay (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Another approach uses stem antigens that lack the globular head as soluble trimeric proteins (17), or perhaps incorporating them into ferritin nanoparticles for immunization purposes to elicit stem-specific antibodies (18). The third approach uses the glycan shielding on the variable regions in the HA globular head to redirect the immune responses to the more conserved HA stem region (19)(20)(21). Several reports also indicate that the HA stem-based influenza vaccines provide cross-subtype protection against diverse group 1 strains but not against diverse group 2 strains (15)(16)(17)(18).…”

mentioning

confidence: 99%

See 2 more Smart Citations

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

Liu

Jan

Huang

et al. 2016

J Virol

View full text Add to dashboard Cite

Influenza virus hemagglutinin (HA) protein consists of two components, i.e., a globular head region and a stem region that are folded within six disulfide bonds, plus several N-linked glycans that produce a homotrimeric complex structure. While N-linked glycosylation sites on the globular head are variable among different strains and different subtypes, N-linked glycosylation sites in the stem region are mostly well conserved among various influenza virus strains. Targeting highly conserved HA stem regions has been proposed as a useful strategy for designing universal influenza vaccines. Since the HA stem region is constituted by an HA1 N-terminal part and a full HA2 part, we expressed a series of recombinant HA mutant proteins with deleted N-linked glycosylation sites in the HA1 stem and HA2 stem regions of H5N1 and pH1N1 viruses. Unmasking N-glycans in the HA2 stem region (H5 N484A and H1 N503A) was found to elicit more potent neutralizing antibody titers against homologous, heterologous, and heterosubtypic viruses. Unmasking the HA2 stem N-glycans of H5HA but not H1HA resulted in more CR6261-like and FI6v3-like antibodies and also correlated with the increase of cell fusion inhibition activity in antisera. Only H5 N484A HA2 stem mutant protein immunization increased the numbers of antibody-secreting cells, germinal center B cells, and memory B cells targeting the stem helix A epitopes in splenocytes. Unmasking the HA2 stem N-glycans of H5HA mutant proteins showed a significantly improvement in the protection against homologous virus challenges but did so to a less degree for the protection against heterosubtypic pH1N1 virus challenges. These results may provide useful information for designing more effective influenza vaccines.

show abstract

Section: Discussionmentioning

confidence: 73%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

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

Liu

Jan

Huang

et al. 2016

J Virol

View full text Add to dashboard Cite

show abstract

“…A variety of approaches for eliciting HA stalkspecific antibody responses have been evaluated in animal models with various degrees of success (43,(48)(49)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60). Collectively, these approaches aim to elicit HA stalk-specific responses through tactics that subvert HA globular head immunodominance.…”

Section: Discussionmentioning

confidence: 99%

Sequential Infection in Ferrets with Antigenically Distinct Seasonal H1N1 Influenza Viruses Boosts Hemagglutinin Stalk-Specific Antibodies

Kirchenbaum

Carter

Ross

2016

J Virol

View full text Add to dashboard Cite

Broadly reactive antibodies targeting the conserved hemagglutinin (HA) stalk region are elicited following sequential infection or vaccination with influenza viruses belonging to divergent subtypes and/or expressing antigenically distinct HA globular head domains. Here, we demonstrate, through the use of novel chimeric HA proteins and competitive binding assays, that sequential infection of ferrets with antigenically distinct seasonal H1N1 (sH1N1) influenza virus isolates induced an HA stalk-specific antibody response. Additionally, stalk-specific antibody titers were boosted following sequential infection with antigenically distinct sH1N1 isolates in spite of preexisting, cross-reactive, HA-specific antibody titers. Despite a decline in stalk-specific serum antibody titers, sequential sH1N1 influenza virus-infected ferrets were protected from challenge with a novel H1N1 influenza virus (A/California/07/2009), and these ferrets poorly transmitted the virus to naive contacts. Collectively, these findings indicate that HA stalk-specific antibodies are commonly elicited in ferrets following sequential infection with antigenically distinct sH1N1 influenza virus isolates lacking HA receptor-binding site cross-reactivity and can protect ferrets against a pathogenic novel H1N1 virus. IMPORTANCE The influenza virus hemagglutinin (HA) is a major target of the humoral immune response following infection and The influenza virus is highly contagious and causes an acute respiratory illness, with seasonal epidemics in the human population. Despite global vaccination efforts, influenza remains a major medical issue and is responsible for substantial morbidity and mortality annually. It is estimated that 5 to 20% of the people in the United States contract influenza virus annually, and more than 200,000 people require hospitalization due to influenza-related complications (according to the Centers for Disease Control and Prevention, Atlanta, GA [http://www.cdc.gov/flu/about/qa /disease.htm; accessed 1 September 2015]). The young, the elderly, pregnant females, and those with certain medical conditions are at an increased risk for influenza-associated complications.Current vaccination approaches primarily rely on the induction of antibodies recognizing hemagglutinin (HA) (1). The HA glycoprotein is expressed as a trimeric complex of identical subunits on the surface of influenza virus virions. HA mediates virus attachment and subsequent membrane fusion with target cells (2, 3). Individual HA monomers can be further segregated into the membrane-distal globular head and membrane-proximal stalk domains. The globular head encodes the receptor-binding site (RBS), and the stalk domain encodes the fusion peptide (2).Antibodies directed against HA and, more specifically, to epitopes in close proximity to the RBS within the globular head region are elicited following infection or vaccination (4). These antibodies possess a potent neutralization capacity through the ability to interfere with viral attachment to target cells and a...

show abstract

“…The stem region is highly conserved among influenza viruses, and anti-stem Abs tend to mediate their neutralization activity by either blocking viral fusion with, or preventing cleavage of, the HA protein (24,25). Vaccine regimens that target the HA stem region have given promising results in mouse models but have yet to be translated into human clinical studies (26)(27)(28).…”

mentioning

confidence: 99%

Influenza-Specific Antibody-Dependent Cellular Cytotoxicity: Toward a Universal Influenza Vaccine

Jegaskanda

Reading

Kent

2014

The Journal of Immunology

116

137

View full text Add to dashboard Cite

There is an urgent need for universal influenza vaccines that can control emerging pandemic influenza virus threats without the need to generate new vaccines for each strain. Neutralizing Abs to the influenza virus hemagglutinin glycoprotein are effective at controlling influenza infection but generally target highly variable regions. Abs that can mediate other functions, such as killing influenza-infected cells and activating innate immune responses (termed “Ab-dependent cellular cytotoxicity [ADCC]-mediating Abs”), may assist in protective immunity to influenza. ADCC-mediating Abs can target more conserved regions of influenza virus proteins and recognize a broader array of influenza strains. We review recent research on influenza-specific ADCC Abs and their potential role in improved influenza-vaccination strategies.

show abstract

Guiding the Immune Response against Influenza Virus Hemagglutinin toward the Conserved Stalk Domain by Hyperglycosylation of the Globular Head Domain

Cited by 162 publications

References 37 publications

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

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

Sequential Infection in Ferrets with Antigenically Distinct Seasonal H1N1 Influenza Viruses Boosts Hemagglutinin Stalk-Specific Antibodies

Influenza-Specific Antibody-Dependent Cellular Cytotoxicity: Toward a Universal Influenza Vaccine

Contact Info

Product

Resources

About