Fc functional antibodies in humans with severe H7N9 and seasonal influenza
Hillary A. Vanderven, Lu Liu, Fernanda Ana-Sosa-Batiz, Thi H.O. Nguyen, Yanmin Wan, Bruce Wines, P. Mark Hogarth, Danielle Tilmanis, Arnold Reynaldi, Matthew S. Parsons, Aeron C. Hurt, Miles P. Davenport, Tom Kotsimbos, Allen C. Cheng, Katherine Kedzierska, Xiaoyan Zhang, Jianqing Xu, Stephen J. Kent
Hillary A. Vanderven, Lu Liu, Fernanda Ana-Sosa-Batiz, Thi H.O. Nguyen, Yanmin Wan, Bruce Wines, P. Mark Hogarth, Danielle Tilmanis, Arnold Reynaldi, Matthew S. Parsons, Aeron C. Hurt, Miles P. Davenport, Tom Kotsimbos, Allen C. Cheng, Katherine Kedzierska, Xiaoyan Zhang, Jianqing Xu, Stephen J. Kent
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Clinical Research and Public Health Immunology Infectious disease

Fc functional antibodies in humans with severe H7N9 and seasonal influenza

Abstract

BACKGROUND. Both seasonal and novel avian influenza viruses can result in severe infections requiring hospitalization. Anti-influenza antibodies (Abs) with Fc-mediated effector functions, such as Ab-dependent cellular cytotoxicity (ADCC), are of growing interest in control of influenza but have not previously been studied during severe human infections. As such, the objective of this study was to examine Fc-mediated Ab functions in humans hospitalized with influenza infection. METHODS. Serum Ab response was studied in subjects hospitalized with either pandemic H7N9 avian influenza virus in China (n = 18) or circulating seasonal influenza viruses in Melbourne, Australia (n = 16). Recombinant soluble Fc receptor dimer ELISAs, natural killer (NK) cell activation assays, and Ab-dependent killing assays with influenza-infected target cells were used to assess the Fc functionality of anti-influenza hemagglutinin (HA) Abs during severe human influenza infection. RESULTS. We found that the peak generation of Fc functional HA Abs preceded that of neutralizing Abs for both severe H7N9 and seasonal influenza infections. Subjects who succumbed to complications of H7N9 infection demonstrated reduced HA-specific Fc receptor–binding Abs (in magnitude and breadth) immediately prior to death compared with those who survived. Subjects who recovered from H7N9 and severe seasonal influenza infections demonstrated increased Fc receptor–binding Abs not only against the homologous infecting strain but against HAs from different influenza A subtypes. CONCLUSION. Collectively, survivors of severe influenza infection rapidly generate a functional Ab response capable of mediating ADCC against divergent influenza viruses. Broadly binding HA Abs with Fc-mediated functions may be a useful component of protective immunity to severe influenza infection. FUNDING. The National Health and Medical Research Council ([NHMRC] grants 1023294, 1041832, and 1071916), the Australian Department of Health, and the joint University of Melbourne/Fudan University International Research and Research Training Fund provided funding for this study.

Authors

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

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Figure 1

Increased HA-specific rsFcγR dimer–binding Abs after severe influenza infections.

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Increased HA-specific rsFcγR dimer–binding Abs after severe influenza in...
Subjects infected with H7N9 influenza (A and C) and seasonal influenza (B and D) were examined for dimeric rsFcγRIIIa (A and B) and rsFcγRIIa (C and D) binding to Ab-opsonized HA at hospital admission, hospital release/death, and approximately 30 days after hospitalization (seasonal infection only). Dimeric rsFcγR binding by Abs to the HA protein of A/Shanghai/1/2013 (H7N9) is shown for 18 H7N9-infected (black circles) and 11 healthy age-matched control (black diamonds) subjects (A and C). For seasonal influenza-infected subjects (B and D), dimeric rsFcγR engagement by Abs was measured against either (a) H1 protein from A/California/04/2009 (H1N1) virus for subjects infected with seasonal H1N1 influenza (4 subjects, gray squares), (b) H3 protein from A/Switzerland/9715293/2013 (H3N2) virus for subjects infected with seasonal H3N2 influenza (8 subjects, black circles), or (c) HA protein from B/Phuket/3073/2013 virus for seasonal influenza B–infected subjects (4 subjects, white triangles). As controls for seasonal influenza, 10 hospitalized influenza-negative subjects (B and D, black diamonds) were tested for dimeric rsFcγR binding by Abs against all 3 seasonal HA proteins. All influenza-infected and control subjects were also tested for dimeric rsFcγR binding by Abs against an irrelevant HIV-1 protein gp140, and representative data are shown for a single time point (all control gp140-specific responses are shown in Supplemental Figure 1). A Kruskal-Wallis test was used to compare healthy age-matched controls to H7N9-infected subjects at hospital admission and hospital release/death, while a Wilcoxon matched-pairs signed-rank test was used to compare rsFcγR dimer binding between hospital admission and hospital release/death samples in the H7N9-infected subjects (A and C). A Mann Whitney U test was used to compare hospitalized seasonal influenza-infected subjects with hospitalized influenza-negative subjects at the same time point of collection (B and D). **P < 0.01, ***P < 0.001.