Heterosubtypic antibody recognition of the influenza virus hemagglutinin receptor binding site enhanced by avidity

Lee, Peter S.; Yoshida, Reiko; Ekiert, D.C.; Sakai, Naoki; Suzuki, Yasuhiko; Takada, Ayato; Wilson, Ian A.

doi:10.1073/pnas.1212371109

Cited by 170 publications

(218 citation statements)

References 45 publications

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“…In addition, access to a conserved epitope using different modes of binding and varied angles of approach is an emerging theme for glycan-dependent antibody recognition of HIV-1 Env (33) and has defined a supersite of vulnerability on HIV-1. This concept is emulated here for influenza virus, where stem antibodies approach the epitope in different ways and use distinct interactions but have functionally similar modes of neutralization, as also observed for bnAbs to the HA receptor binding site (9)(10)(11)(13)(14)(15).…”

Section: Discussionmentioning

confidence: 99%

“…Identification of antigenic sites on HA indicates that influenza antibodies are primarily directed against the immunodominant HA head region (7), which mediates endosomal uptake of the virus into host cells by binding to sialic acid receptors (8). Because of high mutation rates in the HA head region and its tolerance for antigenic changes, antibodies that target the HA head are typically only effective against strains closely related to the strain(s) by which they were elicited, although several receptor binding site-targeting antibodies with greater breadth have been structurally characterized (9)(10)(11)(12)(13)(14)(15). In contrast, antibodies that bind to the membrane-proximal HA stem region tend to exhibit much broader neutralizing activity and can target strains within entire subtypes and groups (16)(17)(18)(19)(20)(21)(22)(23)(24)(25) as well as across influenza types (24).…”

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confidence: 99%

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A common solution to group 2 influenza virus neutralization

Friesen

Lee

Stoop

et al. 2013

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

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170

164

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The discovery and characterization of broadly neutralizing antibodies (bnAbs) against influenza viruses have raised hopes for the development of monoclonal antibody (mAb)-based immunotherapy and the design of universal influenza vaccines. Only one human bnAb (CR8020) specifically recognizing group 2 influenza A viruses has been previously characterized that binds to a highly conserved epitope at the base of the hemagglutinin (HA) stem and has neutralizing activity against H3, H7, and H10 viruses. Here, we report a second group 2 bnAb, CR8043, which was derived from a different germ-line gene encoding a highly divergent amino acid sequence. CR8043 has in vitro neutralizing activity against H3 and H10 viruses and protects mice against challenge with a lethal dose of H3N2 and H7N7 viruses. The crystal structure and EM reconstructions of the CR8043-H3 HA complex revealed that CR8043 binds to a site similar to the CR8020 epitope but uses an alternative angle of approach and a distinct set of interactions. The identification of another antibody against the group 2 stem epitope suggests that this conserved site of vulnerability has great potential for design of therapeutics and vaccines.antibody recognition | X-ray crystallography | electron microscopy

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

A common solution to group 2 influenza virus neutralization

Friesen

Lee

Stoop

et al. 2013

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

Self Cite

170

164

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“…Importantly, this vaccination strategy also induced high titers of stalk-reactive antibodies against the H7 HA from the emerging Chinese H7N9 virus (10). Recently, broadly reactive anti-head antibodies have also been described in the literature (35)(36)(37), and it is theoretically possible that such antibodies are induced by the cHA vaccination regimen. However, we did not detect such antibodies in sera from cHA-immunized animals, suggesting that these antibodies are not induced significantly by this vaccine.…”

Section: Discussionmentioning

confidence: 99%

“…Broadly reactive anti-globular head antibodies have recently been described in the literature (35)(36)(37). Though rare in nature, these antibodies tend to recognize conserved regions of the receptor-binding site and recognize divergent globular head domains without closely following phylogenetic relatedness.…”

Section: Figmentioning

confidence: 99%

Hemagglutinin Stalk-Based Universal Vaccine Constructs Protect against Group 2 Influenza A Viruses

Margine

Krammer

Hai

et al. 2013

J Virol

186

161

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f Current influenza virus vaccines contain H1N1 (phylogenetic group 1 hemagglutinin), H3N2 (phylogenetic group 2 hemagglutinin), and influenza B virus components. These vaccines induce good protection against closely matched strains by predominantly eliciting antibodies against the membrane distal globular head domain of their respective viral hemagglutinins. This domain, however, undergoes rapid antigenic drift, allowing the virus to escape neutralizing antibody responses. The membrane proximal stalk domain of the hemagglutinin is much more conserved compared to the head domain. In recent years, a growing collection of antibodies that neutralize a broad range of influenza virus strains and subtypes by binding to this domain has been isolated. Here, we demonstrate that a vaccination strategy based on the stalk domain of the H3 hemagglutinin (group 2) induces in mice broadly neutralizing anti-stalk antibodies that are highly cross-reactive to heterologous H3, H10, H14, H15, and H7 (derived from the novel Chinese H7N9 virus) hemagglutinins. Furthermore, we demonstrate that these antibodies confer broad protection against influenza viruses expressing various group 2 hemagglutinins, including an H7 subtype. Through passive transfer experiments, we show that the protection is mediated mainly by neutralizing antibodies against the stalk domain. Our data suggest that, in mice, a vaccine strategy based on the hemagglutinin stalk domain can protect against viruses expressing divergent group 2 hemagglutinins.

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“…Head-binding antibodies typically recognize variable loop regions surrounding the receptor site and show serotype-specific neutralization (1,17,18), although some can neutralize a limited set of viral serotypes (19)(20)(21). In contrast, stem-binding antibodies recognize an epitope region that is highly conserved between influenza strains and possess a broad neutralization capacity across many viral subtypes (19,(22)(23)(24)(25)(26) or even across groups (19,27,28).…”

mentioning

confidence: 99%

Relating influenza virus membrane fusion kinetics to stoichiometry of neutralizing antibodies at the single-particle level

Otterstrom

Brandenburg

Koldijk

et al. 2014

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

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The ability of antibodies binding the influenza hemagglutinin (HA) protein to neutralize viral infectivity is of key importance in the design of next-generation vaccines and for prophylactic and therapeutic use. The two antibodies CR6261 and CR8020 have recently been shown to efficiently neutralize influenza A infection by binding to and inhibiting the influenza A HA protein that is responsible for membrane fusion in the early steps of viral infection. Here, we use single-particle fluorescence microscopy to correlate the number of antibodies or antibody fragments (Fab) bound to an individual virion with the capacity of the same virus particle to undergo membrane fusion. To this end, individual, infectious virus particles bound by fluorescently labeled antibodies/ Fab are visualized as they fuse to a planar, supported lipid bilayer. The fluorescence intensity arising from the virus-bound antibodies/ Fab is used to determine the number of molecules attached to viral HA while a fluorescent marker in the viral membrane is used to simultaneously obtain kinetic information on the fusion process. We experimentally determine that the stoichiometry required for fusion inhibition by both antibody and Fab leaves large numbers of unbound HA epitopes on the viral surface. Kinetic measurements of the fusion process reveal that those few particles capable of fusion at high antibody/Fab coverage display significantly slower hemifusion kinetics. Overall, our results support a membrane fusion mechanism requiring the stochastic, coordinated action of multiple HA trimers and a model of fusion inhibition by stem-binding antibodies through disruption of this coordinated action.influenza | neutralizing antibody | hemagglutinin | neutralization stoichiometry | membrane fusion

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Heterosubtypic antibody recognition of the influenza virus hemagglutinin receptor binding site enhanced by avidity

Cited by 170 publications

References 45 publications

A common solution to group 2 influenza virus neutralization

A common solution to group 2 influenza virus neutralization

Hemagglutinin Stalk-Based Universal Vaccine Constructs Protect against Group 2 Influenza A Viruses

Relating influenza virus membrane fusion kinetics to stoichiometry of neutralizing antibodies at the single-particle level

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