Highly Conserved Protective Epitopes on Influenza B Viruses

Dreyfus, Cyrille; Laursen, N.S.; Kwaks, Ted; Zuijdgeest, David; Khayat, Reza; Ekiert, D.C.; Lee, Jeong Hyun; Metlagel, Zoltan; Bujny, Miriam V.; Jongeneelen, Mandy; Vlugt, R. van der; Lamrani, Mohammed; Korse, Hans J. W. M.; Geelen, Eric; Sahin, Özcan; Sieuwerts, Martijn; Brakenhoff, Just P. J.; Vogels, Ronald; Li, Olive T. W.; Poon, Leo L. M.; Peiris, Malik; Koudstaal, Wouter; Ward, Andrew B.; Wilson, Ian A.; Goudsmit, Jaap; Friesen, Robert H.

doi:10.1126/science.1222908

Cited by 718 publications

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“…In contrast to viruses that display icosahedral symmetry, influenza virions are pleiomorphic and thus refractory to computational methods that have proven successful in structural determination of symmetrical viruses using X-ray crystallography or cryoelectron microscopy (21,22). Our present knowledge of HA structure is thus derived largely from crystallographic analyses of soluble ectodomains of trimeric HA or EM analyses of chemically stained HA trimers (23,24). However, the binding of Fab fragments to isolated HA ectodomains might not reflect antibody accessibility to native HA trimers displayed on intact viruses, or allow determination of the extent to which various neutralizing antibodies can access their epitopes in the context of intact virions.…”

mentioning

confidence: 99%

Structure and accessibility of HA trimers on intact 2009 H1N1 pandemic influenza virus to stem region-specific neutralizing antibodies

Harris

Meyerson

Matsuoka³

et al. 2013

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

101

113

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Rapid antigenic variation of HA, the major virion surface protein of influenza A virus, remains the principal challenge to the development of broader and more effective vaccines. Some regions of HA, such as the stem region proximal to the viral membrane, are nevertheless highly conserved across strains and among most subtypes. A fundamental question in vaccine design is the extent to which HA stem regions on the surface of the virus are accessible to broadly neutralizing antibodies. Here we report 3D structures derived from cryoelectron tomography of HA on intact 2009 H1N1 pandemic virions in the presence and absence of the antibody C179, which neutralizes viruses expressing a broad range of HA subtypes, including H1, H2, H5, H6, and H9. By fitting previously derived crystallographic structures of trimeric HA into the density maps, we deduced the locations of the molecular surfaces of HA involved in interaction with C179. Using computational methods to distinguish individual unliganded HA trimers from those that have bound C179 antibody, we demonstrate that ∼75% of HA trimers on the surface of the virus have C179 bound to the stem domain. Thus, despite their close packing on the viral membrane, the majority of HA trimers on intact virions are available to bind anti-stem antibodies that target conserved HA epitopes, establishing the feasibility of universal influenza vaccines that elicit such antibodies.envelope glycoproteins | subvolume averaging | virus structure | hemagglutunin | cryo-electron microscopy

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mentioning

confidence: 99%

Structure and accessibility of HA trimers on intact 2009 H1N1 pandemic influenza virus to stem region-specific neutralizing antibodies

Harris

Meyerson

Matsuoka³

et al. 2013

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

101

113

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“…In the hemagglutinin inhibition assays (HIAs), a serum dilution of 1:40 is considered protective whereas comparable values were found for an ELISA-based and a colorimetric microneutralization assay; however, these values are not applicable to our assay [13], in particular as it was also shown that ELISA values and HIA values do not correlate, not even within the same subtypes [14]. Moreover, because the majority of heterosubtypic antibodies was found to bind a conserved epitope in the stem of the HA protein and did not interfere with hemagglutination [15,16], they would not be detected by HIAs. Consequently, no direct predictions for heterosubtypic protection can be drawn from our dataset at this point.…”

Section: Discussionmentioning

confidence: 82%

Prevalence and Predictors for Homo- and Heterosubtypic Antibodies Against Influenza A Virus

Kohler¹,

Scherrer²,

Zagordi³

et al. 2014

Clinical Infectious Diseases

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Background. The effectiveness of trivalent influenza vaccination has been confirmed in several studies. To date, it is not known whether repeated exposure and vaccination to influenza promote production of cross-reactive antibodies. Furthermore, how strains encountered earlier in life imprint the immune response is currently poorly understood.Methods. To determine the prevalence for human homo-and heterosubtypic antibody responses, we scrutinized serum samples from 305 healthy volunteers for hemagglutinin-binding and -neutralizing antibodies against several strains and subtypes of influenza A. Statistical analyses were then performed to establish the association of measured values with potential predictors.Results. It was found that vaccination not only promoted higher binding and neutralizing antibody titers to homosubtypic influenza isolates but also increased heterosubtypic human immune responses. Both binding and neutralizing antibody titers in relation with age of the donors mirrored the course of the different influenza strain circulation during the last century. Advanced age appeared to be of advantage for both binding and neutralizing titers to most subtypes. In contrast, the first virus subtype encountered was found to imprint to some degree subsequent antibody responses. Antibodies to recent strains, however, primarily seemed to be promoted by vaccination.Conclusions. We provide evidence that vaccinations stimulate both homo-and heterosubtypic immune responses in young and middle-aged as well as more senior individuals. Our analyses suggest that influenza vaccinations not only prevent infection against currently circulating strains but can also stimulate broader humoral immune responses that potentially attenuate infections with zoonotic or antigenically shifted strains.

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“…Les noms de l'ensemble des virus testés lors de notre étude sont indiqués (adapté de [3]). chement du virus aux acides sialiques présents à la surface de la cellule cible, ainsi qu'à la fusion de la membrane virale et de la membrane cellulaire après endocytose (Figure 2 …”

Section: La Diversité Génétique Des Virus De La Grippe Un Frein Au Dunclassified

“…Les virus influenza B ne ségrègent pas en sous-types, mais leur évolution est caractérisée par la cocirculation de deux lignées possé-dant des caractéristiques génétiques et antigéniques différentes ( Figure 1B) [7]. L'HA, une glycoprotéine antigé-nique présente à la surface du virus de la grippe, est nécessaire à l'atta-A (bnAb, broadly neutralizing antibodies) [2][3][4][5][6] [2,4,6]. Cette région hautement conservée se situe au niveau de la partie de l'HA proche de la membrane appelée stem 1 (Figure 3).…”

Section: L'hémagglutinine : Cible Des Anticorps Neutralisantsunclassified

“…Cette région hautement conservée se situe au niveau de la partie de l'HA proche de la membrane appelée stem 1 (Figure 3). Contrairement aux précédents anticorps, CR9114 reconnaît un épitope conservé non seulement chez tous les virus influenza A, mais aussi chez les virus influenza B. L'analyse des déterminants moléculaires de l'interaction entre CR9114 et l'HA nous a révélé comment, via son mode de liaison, CR9114 est capable de neutraliser une telle diversité de virus [3]. Les anticorps reconnaissant cette région de l'HA neutralisent le virus par un méca-nisme nouveau, en bloquant le changement conformationnel de l'HA nécessaire à la fusion de la membrane virale avec celle de l'endosome durant le processus d'entrée du virus.…”

Section: L'hémagglutinine : Cible Des Anticorps Neutralisantsunclassified

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