Fc functional antibodies in humans with severe H7N9 and seasonal influenza

Vanderven, Hillary A.; Liu, Lu; Ana-Sosa-Batiz, Fernanda; Nguyen, Thi H. O.; Wan, Yanmin; Wines, Bruce D.; Hogarth, P. Mark; Tilmanis, Danielle; Reynaldi, Arnold; Parsons, Matthew S.; Hurt, Aeron C.; Davenport, Miles P.; Kotsimbos, Tom; Cheng, Allen; Kedzierska, Katherine; Zhang, Xiaoyan; Xu, Jianqing; Kent, Stephen J.

doi:10.1172/jci.insight.92750

Cited by 45 publications

(48 citation statements)

References 52 publications

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“…47 For HIV, ADCC-inducing antibodies have been identified as a key correlate of protection in the RV144 HIV vaccine trial. [48][49][50] For influenza, the role of ADCC was shown to be protective in some studies, 51,52 but others point to the involvement of ADCC in exaggeration of the immune response. [53][54][55] Taken together, these examples show that the capacity of pathogenspecific antibodies to engage NK cells can significantly contribute to the outcome of infection.…”

Section: Discussionmentioning

confidence: 99%

Natural killer cell activation by respiratory syncytial virus‐specific antibodies is decreased in infants with severe respiratory infections and correlates with Fc‐glycosylation

et al. 2020

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Objectives Respiratory syncytial virus (RSV) is a major cause of severe lower respiratory tract infections in infants, and there is no vaccine available. In early life, the most important contributors to protection against infectious diseases are the innate immune response and maternal antibodies. However, antibody‐mediated protection against RSV disease is incompletely understood, as both antibody levels and neutralisation capacity correlate poorly with protection. Since antibodies also mediate natural killer (NK) cell activation, we investigated whether this functionality correlates with RSV disease. Methods We performed an observational case–control study including infants hospitalised for RSV infection, hernia surgery or RSV‐negative respiratory viral infections. We determined RSV antigen‐specific antibody levels in plasma using a multiplex immunoassay. Subsequently, we measured the capacity of these antibodies to activate NK cells. Finally, we assessed Fc‐glycosylation of the RSV‐specific antibodies by mass spectrometry. Results We found that RSV‐specific maternal antibodies activate NK cells in vitro. While concentrations of RSV‐specific antibodies did not differ between cases and controls, antibodies from infants hospitalised for severe respiratory infections (RSV and/or other) induced significantly less NK cell interferon‐γ production than those from uninfected controls. Furthermore, NK cell activation correlated with Fc‐fucosylation of RSV‐specific antibodies, but their glycosylation status did not significantly differ between cases and controls. Conclusion Our results suggest that Fc‐dependent antibody function and quality, exemplified by NK cell activation and glycosylation, contribute to protection against severe RSV disease and warrant further studies to evaluate the potential of using these properties to evaluate and improve the efficacy of novel vaccines.

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Section: Discussionmentioning

confidence: 99%

Natural killer cell activation by respiratory syncytial virus‐specific antibodies is decreased in infants with severe respiratory infections and correlates with Fc‐glycosylation

et al. 2020

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show abstract

“…For HIV, ADCC-inducing antibodies have been identified as a key correlate of protection in the RV144 HIV vaccine trial (44-46). For influenza, the role of ADCC was shown to be protective in some studies (47, 48), but others point to the involvement of ADCC in exaggeration of the immune response (49-51). Taken together, these examples show that the capacity of pathogen-specific antibodies to engage NK cells can significantly contribute to the outcome of infection.…”

Section: Discussionmentioning

confidence: 99%

Natural killer cell activation by respiratory syncytial virus-specific antibodies is decreased in infants with severe respiratory infections and correlates with Fc-glycosylation

Erp

Lakerveld

Graaf

et al. 2019

Preprint

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AbstractBackgroundRespiratory syncytial virus (RSV) is a major cause of severe lower respiratory tract infections in infants and there is no vaccine available. In early life, the most important contributors to protection against infectious diseases are the innate immune system and maternal antibodies. However, the mechanisms by which antibodies can protect against RSV disease are incompletely understood, as both antibody levels and neutralization capacity correlate poorly with protection. We therefore asked whether antibody-mediated natural killer (NK) cell activation correlates with RSV disease.MethodsWe performed an observational case-control study including infants hospitalized for RSV infection (n=43, cases), hernia surgery (n=16, controls), or RSV-negative viral respiratory tract infections (n=18, controls). First, we determined RSV antigen-specific antibody levels in infant plasma using a multiplex immunoassay. Subsequently, we measured the capacity of these antibodies to activate NK cells. Finally, we assessed Fc-glycosylation of the RSV-specific antibodies by mass spectrometry.ResultsWe found that RSV-specific maternal antibodies potently activate NK cells in vitro. While the concentrations of RSV-specific antibodies did not differ between cases and controls, antibodies from infants hospitalized for severe lower respiratory tract infections (RSV and/or other) induced significantly less NK cell interferon gamma production than those from uninfected controls. Furthermore, NK cell activation correlated with Fc-fucosylation of RSV-specific antibodies, but their glycosylation status did not significantly differ between cases and controls.ConclusionsOur results suggest that Fc-dependent antibody function and quality, exemplified by NK cell activation and glycosylation, contribute to protection against severe RSV disease and warrant further studies to evaluate the potential of harnessing these activities to develop an effective vaccine.

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“…The breadth, specificity and function of influenza-specific antibodies are actively shaped by multiple factors, 35,44 such as the route of exposure (e.g. peripheral vaccination versus local infection at mucosal surfaces), T cell help for B cells and inflammation levels of infection.…”

Section: Discussionmentioning

confidence: 99%

Cross‐reactive antibody‐dependent cellular cytotoxicity antibodies are increased by recent infection in a household study of influenza transmission

et al. 2019

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Objectives Influenza causes a spectrum of disease from asymptomatic infection to fatal outcome, and pre‐existing immunity can alter susceptibility and disease severity. In a household transmission study, we recruited outpatients with confirmed influenza virus infection and prospectively identified secondary infections in their household contacts, therefore identifying infection cases with baseline samples for determining immune‐mediated protection from influenza infection. Methods We examined baseline broadly reactive immune correlates of relevance to universal vaccine development, specifically antibody‐dependent cytotoxic (ADCC) antibodies and T‐cell responses in functional assays. Antibodies were assessed in a cell‐based NK cell degranulation assay by flow cytometry, and T‐cell responses were assessed by IFN‐γ intracellular cytokine staining flow cytometry assay. Results The magnitude of antibody responses and ADCC function for multiple influenza‐specific proteins was lower in participants who became infected, consolidating the role of pre‐existing antibodies in protection from seasonal influenza virus infection. Among H1N1‐infected contacts, we found that higher levels of pre‐existing H1‐haemagglutinin ADCC responses correlated with reduced symptom severity. Recent infection boosted the titre and magnitude of haemagglutinin‐, neuraminidase‐ and nucleoprotein‐specific ADCC antibodies. Limited T‐cell samples precluded conclusions on the role of pre‐existing T‐cell responses. Conclusions Overall, ADCC responses are a protective correlate against influenza virus infection that should be considered in future vaccine development and evaluation. Influenza‐specific ADCC responses are elevated in uninfected subjects, associated with reduced symptoms and boosted by recent infection, whilst HA stem and NA IgG are also elevated in uninfected participants irrespective of ADCC function.

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Fc functional antibodies in humans with severe H7N9 and seasonal influenza

Cited by 45 publications

References 52 publications

Natural killer cell activation by respiratory syncytial virus‐specific antibodies is decreased in infants with severe respiratory infections and correlates with Fc‐glycosylation

Natural killer cell activation by respiratory syncytial virus‐specific antibodies is decreased in infants with severe respiratory infections and correlates with Fc‐glycosylation

Natural killer cell activation by respiratory syncytial virus-specific antibodies is decreased in infants with severe respiratory infections and correlates with Fc-glycosylation

Cross‐reactive antibody‐dependent cellular cytotoxicity antibodies are increased by recent infection in a household study of influenza transmission

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