Pan-H7 influenza human antibody virus neutralization depends on avidity and steric hindrance
Iuliia M. Gilchuk, Jinhui Dong, Ryan P. Irving, Cameron D. Buchman, Erica Armstrong, Hannah L. Turner, Sheng Li, Andrew B. Ward, Robert H. Carnahan, James E. Crowe Jr.
Iuliia M. Gilchuk, Jinhui Dong, Ryan P. Irving, Cameron D. Buchman, Erica Armstrong, Hannah L. Turner, Sheng Li, Andrew B. Ward, Robert H. Carnahan, James E. Crowe Jr.
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Research Article Immunology Infectious disease Virology

Pan-H7 influenza human antibody virus neutralization depends on avidity and steric hindrance

Abstract

H7N9 avian influenza virus is a zoonotic influenza virus of public health concern, with a 39% mortality rate in humans. H7N9-specific prevention or treatments for humans have not been approved. We previously isolated a human monoclonal antibody (mAb) designated H7-235 that broadly reacts to diverse H7 viruses and neutralizes H7N9 viruses in vitro. Here, we report the crystal structure of H7 HA1 bound to the fragment antigen-binding region (Fab) of recombinant H7-235 (rH7-235). The crystal structure revealed that rH7-235 recognizes residues near but outside of the receptor binding site (RBS). Nevertheless, the rH7-235 IgG potently inhibits hemagglutination mediated by H7N9 viruses due to avidity effect and Fc steric hindrance. This mAb prophylactically protects mice against weight loss and death caused by challenge with lethal H7N9 viruses in vivo. rH7-235 mAb neutralizing activity alone is sufficient for protection when used at a high dose in a prophylactic setting. This study provides insights into mechanisms of viral neutralization by protective, broadly reactive anti-H7 antibodies, informing the rational design of therapeutics and vaccines against H7N9 influenza virus.

Authors

Iuliia M. Gilchuk, Jinhui Dong, Ryan P. Irving, Cameron D. Buchman, Erica Armstrong, Hannah L. Turner, Sheng Li, Andrew B. Ward, Robert H. Carnahan, James E. Crowe Jr.

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Figure 4

rH7-235 mAb is protective in vivo and Fc-effector function independent at higher mAb dose.

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rH7-235 mAb is protective in vivo and Fc-effector function independent a...
(A–C) Female 18-20 g BALB/c mice were inoculated by the intraperitoneal route with a 10 mg/kg (A-C) or 2 mg/kg (D-E) dose of mAbs: (A-C) rH7-235 IgG1 (n = 20), rH7-235 LALA-PG (n = 20) or a control antibody (DENV 2D22 [negative control] (n = 25) or rMEDI8852 [positive control] (n = 10); (D-E) rH7-235 IgG1 (n = 10), rH7-235 LALA-PG (n = 10) or DENV 2D22 (n = 10). At 24 hours after the mAb treatment, anesthetized mice were inoculated by the intranasal route with 104 focus forming units of H7N9 SH13 (IDCDC-RG32A) virus in 50 µL of sterile PBS. Mice were weighed and monitored daily for body weight change (A, D) and survival (C, E) for 12 days. Those losing over 30% of initial body weight were euthanized humanely as per IACUC requirements. To determine viral replication in lungs of infected mice, 5 animals from H7-235 IgG, LALA-PG and negative control groups were euthanized on day 3 post-infection (B). Data shown are mean with SEM. Comparison of survival curves performed using Kaplan-Meier Method with Log-rank (Mantel-Cox) test using GraphPad Prism 10.3.1. See also Supplemental Figure S4.