Preventing an Antigenically Disruptive Mutation in Egg-Based H3N2 Seasonal Influenza Vaccines by Mutational Incompatibility

Wu, Nicholas C.; Lv, Huibin; Thompson, Andrew J.; Wu, Douglas C.; Ng, Wilfred; Kadam, Rameshwar U.; Lin, Chih Wei; Nycholat, Corwin M.; McBride, Ryan; Liang, Weiwen; Paulson, James C.; Mok, Chris Ka Pun; Wilson, Ian A.

doi:10.1016/j.chom.2019.04.013

Cited by 48 publications

(65 citation statements)

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“…It is therefore not surprising that some of the mutations that arise during natural evolution of human influenza virus can alter both HA antigenicity and receptor binding [47,48,85,86]. Furthermore, egg-based seasonal influenza vaccines often carry egg-adaptive mutations in the HA RBS that allow the vaccine strain to bind to α2-3 linkage sialylated glycans on the chorioallantoic membrane but can also alter the antigenicity of HA, thereby decreasing vaccine effectiveness [49,[87][88][89]. For example, one of the egg-adaptive mutations T160K would abolish an N-glycosylation site at N158 and appears to contribute to the poor seasonal influenza vaccine effectiveness in the 2016-2017 influenza season.…”

Section: Antibodies To Influenza Hamentioning

confidence: 99%

Structural Biology of Influenza Hemagglutinin: An Amaranthine Adventure

Wilson

2020

Viruses

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Hemagglutinin (HA) glycoprotein is an important focus of influenza research due to its role in antigenic drift and shift, as well as its receptor binding and membrane fusion functions, which are indispensable for viral entry. Over the past four decades, X-ray crystallography has greatly facilitated our understanding of HA receptor binding, membrane fusion, and antigenicity. The recent advances in cryo-EM have further deepened our comprehension of HA biology. Since influenza HA constantly evolves in natural circulating strains, there are always new questions to be answered. The incessant accumulation of knowledge on the structural biology of HA over several decades has also facilitated the design and development of novel therapeutics and vaccines. This review describes the current status of the field of HA structural biology, how we got here, and what the next steps might be.

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Section: Antibodies To Influenza Hamentioning

confidence: 99%

Structural Biology of Influenza Hemagglutinin: An Amaranthine Adventure

Wilson

2020

Viruses

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“…In addition, most seasonal influenza vaccines are produced in embryonated chicken eggs, which may result in HA egg-adaptive mutations that change the antigenicity of the vac-cine strains (Robertson et al 1987;Kodihalli et al 1995;Chen et al 2010;Popova et al 2012;Parker et al 2016;Raymond et al 2016;Zost et al 2017). Egg-adaptation mutations allow HAs from human influenza viruses, which has a receptor specificity toward α2,6-linked sialic acid, to increase affinity to α2,3-linked sialic acid (Wu et al , 2019, which is abundant on the chorioallantoic membrane (Ito et al 1997;Sriwilaijaroen et al 2009). As a result, the effectiveness of seasonal influenza vaccine is far from satisfying (Belongia et al 2016).…”

Section: Vaccines Against Hemagglutininmentioning

confidence: 99%

Influenza Hemagglutinin Structures and Antibody Recognition

Wilson

2019

Cold Spring Harb Perspect Med

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Hemagglutinin (HA) is most abundant glycoprotein on the influenza virus surface. Influenza HA promotes viral entry by engaging the receptor and mediating virus-host membrane fusion. At the same time, HA is the major antigen of the influenza virus. HA antigenic shift can result in pandemics, whereas antigenic drift allows human circulating strains to escape herd immunity. Most antibody responses against HA are strain-specific. However, antibodies that have neutralizing activities against multiple strains or even subtypes have now been discovered and characterized. These broadly neutralizing antibodies (bnAbs) target conserved regions on HA, such as the receptor-binding site and the stem domain. Structural studies of such bnAbs have provided important insight into universal influenza vaccine and therapeutic design. This review discusses the HA functions as well as HA-antibody interactions from a structural perspective.

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“…Current vaccines induce narrow, strain-specific responses predominantly targeting the hypervariable head domain of HA, and lose efficacy from one season to the next due to antigenic variation. Vaccine performance is also blunted when antigenic mismatches occur between the vaccine and circulating strains arising from mispredictions or egg-adapted mutations introduced during vaccine manufacturing [5][6][7][8][9] . These challenges require continual updating of the vaccine strains and annual vaccine reformulation.…”

Section: Introductionmentioning

confidence: 99%

Elicitation of broadly protective immunity to influenza by multivalent hemagglutinin nanoparticle vaccines

Boyoglu-Barnum

Ellis

Gillespie

et al. 2020

Preprint

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Influenza vaccines that confer broad and durable protection against diverse virus strains would have a major impact on global health. However, next-generation vaccine design efforts have been complicated by challenges including the genetic plasticity of the virus and the immunodominance of certain epitopes in its glycoprotein antigens. Here we show that computationally designed, two-component nanoparticle immunogens induce potently neutralizing and broadly protective antibody responses against a wide variety of influenza viruses. The nanoparticle immunogens display 20 hemagglutinin (HA) trimers in a highly immunogenic array, and their assembly in vitro enables precisely controlled co-display of multiple distinct HAs in defined ratios. Nanoparticle immunogens displaying the four HAs of licensed quadrivalent influenza vaccines (QIV) elicited hemagglutination inhibition and neutralizing antibody responses to vaccine-matched strains that were equivalent or superior to commercial QIV in mice, ferrets, and nonhuman primates. The nanoparticle immunogens—but not QIV—simultaneously induced broadly protective antibody responses to heterologous viruses, including H5N1 and H7N9, by targeting the subdominant yet conserved HA stem. Unlike previously reported influenza vaccine candidates, our nanoparticle immunogens can alter the intrinsic immunodominance hierarchy of HA to induce both potent receptor-blocking and broadly cross-reactive stem-directed antibody responses and are attractive candidates for a next-generation influenza vaccine that could replace current seasonal vaccines.One Sentence SummaryNanoparticle immunogens displaying four seasonal influenza hemagglutinins elicit neutralizing antibodies directed at both the immunodominant head and the conserved stem and confer broad protective immunity.

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Preventing an Antigenically Disruptive Mutation in Egg-Based H3N2 Seasonal Influenza Vaccines by Mutational Incompatibility

Cited by 48 publications

References 47 publications

Structural Biology of Influenza Hemagglutinin: An Amaranthine Adventure

Structural Biology of Influenza Hemagglutinin: An Amaranthine Adventure

Influenza Hemagglutinin Structures and Antibody Recognition

Elicitation of broadly protective immunity to influenza by multivalent hemagglutinin nanoparticle vaccines

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