Enhanced Potency of a Broad H7N9-Neutralizing Antibody HNIgGA6 Through Structure-Based Design.

Cong Chen,Jianmin Wang,Liguo Liu,Qi Jin,Zuliang Liu

doi:10.3389/fmicb.2020.01313

Abstract

H7N9 influenza virus was first isolated in 2013 and has caused five epidemic waves among humans to date. Treatment opinions are currently limited. Previously, we characterized a human neutralizing antibody, HNIgGA6, by isolating rearranged heavy- and light-chain genes from convalescent patients. The mAb disrupts viral attachment to the cellular receptor by directly interposing into the receptor binding site (RBS) and broadly neutralizing divergent H7N9 strains. To increase the protective efficacy of HNIgGA6, we employed a structure-based design to enhance its binding affinity and neutralization potency. When the serine at position 28 on light-chain complementarity-determining region 1 (LCDR1) was substituted by a histidine, compared to HNIgGA6, the mutated antibody showed an approximately three-fold increase in HA-binding affinity and 10-fold enhancement in neutralization potency in vitro. Importantly, the S28H variant also exhibited broad H7N9-neutralizing activity. When administered to BALB/c mice, mAb S28H showed enhanced potency in inhibiting the pulmonary virus titre and reducing lung lesions and resulted in better protection of the animals than did the original antibody.

Highlights

Avian influenza virus (AIV) uses birds or poultry as natural reservoirs and circulates among humans, causing acute respiratory infections
When the residue was substituted with arginine, the viral receptor binding site (RBS) could bind to residue G99 in HCDR3 via hydrogen bonds and stabilize the antibody conformation (Figure 1C)
In the first few days, a pronounced weight loss was observed in the antibodytreated groups; the mice gradually restored their body weights, suggesting the recovery of the infected animals (Figure 5B). These results demonstrated that HNIgGA6 and its S28H mutant substantially decreased the mortality and morbidity of mice infected with H7N9

Summary

Introduction

Avian influenza virus (AIV) uses birds or poultry as natural reservoirs and circulates among humans, causing acute respiratory infections. In March 2013, a reassortment H7N9 AIV subtype was first isolated in China and found to be highly contagious and lethal to humans (Liu et al, 2013; Rongbao et al, 2013). Five major epidemic waves have been reported, resulting in a total of 1564 laboratory-confirmed human cases and at least 615. A sudden increase in the number of human infections (688 cases) and a much broader distribution in the fifth wave was observed, causing concerns of a possible H7N9 pandemic (Quan et al, 2018). H7N9 AIV is classified as “an unusually dangerous virus for humans” by the World Health Organization (WHO, 3)

Methods

Results

Conclusion