Defining the antibody cross-reactome directed against the influenza virus surface glycoproteins

Nachbagauer, Raffael; Choi, Angela; Hirsh, Ariana; Margine, Irina; Iida, Sei‐ichi; Barrera, Aldo; Ferrés, Marcela; Albrecht, Randy A.; García‐Sastre, Adolfo; Bouvier, Nicole M.; Ito, Kimihito; Medina, Rafael; Palese, Peter; Krammer, Florian

doi:10.1038/ni.3684

Cited by 149 publications

(194 citation statements)

References 45 publications

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“…For instance, H1N1 influenza infections have been shown to induce a significantly broader antibody response compared to infections with other strains, including seasonal H3N2 viruses. 39 In HIV, bNAbs targeting the CD4-binding site are significantly more prevalent in infections with subtype B viruses, while bNAbs targeting the V2 glycan are associated with non-subtype B viruses. 23 Efforts to develop HCV vaccines have focused on GT1-based envelope formulations, primarily due to the worldwide prevalence of this genotype.…”

Section: Discussionmentioning

confidence: 99%

B cell immunodominance in primary hepatitis C virus infection

Brasher

Eltahla

Underwood

et al. 2020

Journal of Hepatology

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B cell immunodominance in primary hepatitis C virus infectionGraphical abstract Immunodominance of anti-HCV E1E2 antibodies measured in 168 patientsHighlights Neutralising antibodies will likely form a key component of an HCV vaccine.We characterise the immunodominance of neutralising and non-neutralising epitopes in primary HCV infection.We identify that virus genotype might influence the epitopes targeted.We also identify that certain epitope target combinations are associated with greater breadth.Background & Aims: Neutralising antibodies (NAbs) play a key role in clearance of HCV. NAbs have been isolated and mapped to several domains on the HCV envelope proteins. However, the immunodominance of these epitopes in HCV infection remains unknown, hindering efforts to elicit optimal epitope-specific responses. Furthermore, it remains unclear which epitopespecific responses are associated with broad NAb (bNAb) activity in primary HCV infection. The aim of this study was to define B cell immunodominance in primary HCV, and its implications on neutralisation breadth and clearance. Methods: Using samples from 168 patients with primary HCV infection, the antibody responses targeted 2 immunodominant domains, termed domains B and C. Genotype 1 and 3 infections were associated with responses targeted towards different bNAb domains.Results: No epitopes were uniquely targeted by clearers compared to those who developed chronic infection. Samples with bNAb activity were enriched for multi-specific responses directed towards the epitopes antigenic region 3, antigenic region 4, and domain D, and did not target non-neutralising domains.Conclusions: This study outlines for the first time a clear NAb immunodominance profile in primary HCV infection, and indicates that it is influenced by the infecting virus. It also highlights the need for a vaccination strategy to induce multi-specific responses that do not target non-neutralising domains. Lay summary: Neutralising antibodies will likely form a key component of a protective hepatitis C virus vaccine. In this work we characterise the predominant neutralising and nonneutralising antibody (epitope) targets in acute hepatitis C virus infection. We have defined the natural hierarchy of epitope immunodominance, and demonstrated that viral genotype can impact on this hierarchy. Our findings highlight key epitopes that are associated with broadly neutralising antibodies, and the deleterious impact of mounting a response towards some of these domains on neutralising breadth. These findings should guide future efforts to design immunogens aimed at generating neutralising antibodies with a vaccine candidate.

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Section: Discussionmentioning

confidence: 99%

B cell immunodominance in primary hepatitis C virus infection

Brasher

Eltahla

Underwood

et al. 2020

Journal of Hepatology

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“…These antibodies include HA stalk-specific antibodies as well as HI active head-specific antibodies that are directed to the nonclassical antigenic sites (37,58,59). These observations may be explained by immunological imprinting during first exposure to influenza during childhood and repeated exposures to later drifted strains whose major antigenic sites change over time, whereas subdominant epitopes remain relatively constant (60)(61)(62)(63)(64)(65)(66)(67)(68). As a result, seasonal vaccination did not appear to effectively increase protective antibody responses to the vaccine strain (37).…”

Section: Discussionmentioning

confidence: 99%

Development of Influenza B Universal Vaccine Candidates Using the “Mosaic” Hemagglutinin Approach

Sun

Kirkpatrick

Ermler

et al. 2019

J Virol

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Influenza B viruses cause seasonal epidemics and are a considerable burden to public health. However, protection by current seasonal vaccines is suboptimal due to the antigenic changes of the circulating strains. In this study, we report a novel universal influenza B virus vaccination strategy based on "mosaic" hemagglutinins. We generated mosaic B hemagglutinins by replacing the major antigenic sites of the type B hemagglutinin with corresponding sequences from exotic influenza A hemagglutinins and expressed them as soluble trimeric proteins. Sequential vaccination with recombinant mosaic B hemagglutinin proteins conferred crossprotection against both homologous and heterologous influenza B virus strains in the mouse model. Of note, we rescued recombinant influenza B viruses expressing mosaic B hemagglutinins, which could serve as the basis for a universal influenza B virus vaccine. IMPORTANCE This work reports a universal influenza B virus vaccination strategy based on focusing antibody responses to conserved head and stalk epitopes of the hemagglutinin. Recombinant mosaic influenza B hemagglutinin proteins and recombinant viruses have been generated as novel vaccine candidates. This vaccine strategy provided broad cross-protection in the mouse model. Our findings will inform and drive development toward a more effective influenza B virus vaccine.

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“…OAS is explained by the competitive dominance of MBCs reactive to conserved epitopes on the HA head domain (3,21), but experimental support at the level of MBC population dynamics is lacking. In addition to OAS-type Ab production, IAV infection generally induces increased Ab titers against HAs of the infecting virus and related strains (16,(22)(23)(24), but it is unclear whether MBC adaptation to a novel HA occurs.…”

mentioning

confidence: 99%

Broad Hemagglutinin-Specific Memory B Cell Expansion by Seasonal Influenza Virus Infection Reflects Early-Life Imprinting and Adaptation to the Infecting Virus

Tesini

Kanagaiah

Wang

et al. 2019

J Virol

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106

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Memory B cells (MBCs) are key determinants of the B cell response to influenza virus infection and vaccination, but the effect of different forms of influenza antigen exposure on MBC populations has received little attention. We analyzed peripheral blood mononuclear cells and plasma collected following human H3N2 influenza infection to investigate the relationship between hemagglutininspecific antibody production and changes in the size and character of hemagglutininreactive MBC populations. Infection produced increased concentrations of plasma IgG reactive to the H3 head of the infecting virus, to the conserved stalk, and to a broad chronological range of H3s consistent with original antigenic sin responses. H3-reactive IgG MBC expansion after infection included reactivity to head and stalk domains. Notably, expansion of H3 head-reactive MBC populations was particularly broad and reflected original antigenic sin patterns of IgG production. Findings also suggest that early-life H3N2 infection "imprints" for strong H3 stalk-specific MBC expansion. Despite the breadth of MBC expansion, the MBC response included an increase in affinity for the H3 head of the infecting virus. Overall, our findings indicate that H3-reactive MBC expansion following H3N2 infection is consistent with maintenance of response patterns established early in life, but nevertheless includes MBC adaptation to the infecting virus. IMPORTANCE Rapid and vigorous virus-specific antibody responses to influenza virus infection and vaccination result from activation of preexisting virus-specific memory B cells (MBCs).Understanding the effects of different forms of influenza virus exposure on MBC populations is therefore an important guide to the development of effective immunization strategies. We demonstrate that exposure to the influenza hemagglutinin via natural infection enhances broad protection through expansion of hemagglutinin-reactive MBC populations that recognize head and stalk regions of the molecule. Notably, we show that hemagglutinin-reactive MBC expansion reflects imprinting by early-life infection and that this might apply to stalkreactive, as well as to head-reactive, MBCs. Our findings provide experimental

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Defining the antibody cross-reactome directed against the influenza virus surface glycoproteins

Cited by 149 publications

References 45 publications

B cell immunodominance in primary hepatitis C virus infection

B cell immunodominance in primary hepatitis C virus infection

Development of Influenza B Universal Vaccine Candidates Using the “Mosaic” Hemagglutinin Approach

Broad Hemagglutinin-Specific Memory B Cell Expansion by Seasonal Influenza Virus Infection Reflects Early-Life Imprinting and Adaptation to the Infecting Virus

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