Identification of a broad-inhibition influenza neuraminidase antibody from pre-existing memory B cells

Xin Wang; Huihui Kong; Bingxin Chu; Qian Yang; Chaohui Lin; Rui Liu; Changxu Chen; Yang Gao; Guojun Wang; Dayan Wang; Chen Qin; Xiaohua Ye; Lifei Yu; Xiangfei Xu; Jie Jin; Ren Sun; Hualan Chen; Xudong Wu; Zeli Zhang

doi:10.1016/j.chom.2024.12.004

Identification of a broad-inhibition influenza neuraminidase antibody from pre-existing memory B cells

Cell Host Microbe. 2025 Jan 8;33(1):151-166.e8. doi: 10.1016/j.chom.2024.12.004. Epub 2024 Dec 30.

Authors

Xin Wang¹, Huihui Kong², Bingxin Chu³, Qian Yang¹, Chaohui Lin¹, Rui Liu⁴, Changxu Chen⁴, Yang Gao⁵, Guojun Wang⁵, Dayan Wang⁶, Chen Qin², Xiaohua Ye¹, Lifei Yu⁷, Xiangfei Xu⁷, Jie Jin⁷, Ren Sun⁸, Hualan Chen⁹, Xudong Wu¹⁰, Zeli Zhang¹¹

Affiliations

¹ Zhejiang Key Laboratory of Multi-Omics in Infection and Immunity, Center for Infectious Disease Research, School of Medicine, Westlake University, Hangzhou, Zhejiang, China.
² State Key Laboratory for Animal Disease Control, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China.
³ Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China.
⁴ School of Life Science, Westlake University, Hangzhou, Zhejiang, China.
⁵ The State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, College of Life Sciences, Inner Mongolia University, Hohhot, China.
⁶ National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China; WHO Collaborating Center for Reference and Research on Influenza, Beijing, China.
⁷ Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, Zhejiang, China.
⁸ Zhejiang Key Laboratory of Multi-Omics in Infection and Immunity, Center for Infectious Disease Research, School of Medicine, Westlake University, Hangzhou, Zhejiang, China; Research Center for Industries of the Future, Westlake University, Hangzhou, Zhejiang, China; School of Life Science, Westlake University, Hangzhou, Zhejiang, China.
⁹ State Key Laboratory for Animal Disease Control, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China. Electronic address: [email protected].
¹⁰ Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China; Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China; Institute of Biology, Westlake Institute for Advanced Study, Hangzhou, Zhejiang, China. Electronic address: [email protected].
¹¹ Zhejiang Key Laboratory of Multi-Omics in Infection and Immunity, Center for Infectious Disease Research, School of Medicine, Westlake University, Hangzhou, Zhejiang, China; Research Center for Industries of the Future, Westlake University, Hangzhou, Zhejiang, China; School of Life Science, Westlake University, Hangzhou, Zhejiang, China. Electronic address: [email protected].

PMID: 39740671
DOI: 10.1016/j.chom.2024.12.004

Abstract

Identifying broadly reactive B precursor cells and conserved epitopes is crucial for developing a universal flu vaccine. In this study, using influenza neuraminidase (NA) mutant probes, we find that human pre-existing NA-specific memory B cells (MBCs) account for ∼0.25% of total MBCs, which are heterogeneous and dominated by class-unswitched MBCs. In addition, we identify three NA broad-inhibition monoclonal antibodies (mAbs) (BImAbs) that block the activity of NA derived from different influenza strains, including the recent cow H5N1. The cryoelectron microscopy (cryo-EM) structure shows that the BImAb targets the conserved NA enzymatic pocket and a separate epitope in the neighboring NA monomer. Furthermore, the NA BImAbs protect mice from the lethal challenge of the human pandemic H1N1 and H5N1. Our work demonstrates that the NA broad-inhibition precursor MBCs exist in healthy adults and could be targeted by the NA-based universal flu vaccine.

Keywords: broad-inhibition antibody; influenza virus; memory B cells; neuraminidase; pre-existing immunity.

MeSH terms

Animals
Antibodies, Monoclonal* / immunology
Antibodies, Viral* / immunology
Cryoelectron Microscopy
Epitopes / immunology
Female
Humans
Influenza A Virus, H1N1 Subtype* / immunology
Influenza A Virus, H5N1 Subtype* / immunology
Influenza Vaccines* / immunology
Influenza, Human / immunology
Influenza, Human / prevention & control
Influenza, Human / virology
Memory B Cells* / immunology
Mice
Mice, Inbred BALB C
Neuraminidase* / immunology
Orthomyxoviridae Infections* / immunology
Orthomyxoviridae Infections* / prevention & control
Orthomyxoviridae Infections* / virology
Viral Proteins / immunology

Substances

Neuraminidase
Antibodies, Viral
Antibodies, Monoclonal
Influenza Vaccines
Viral Proteins
Epitopes