Influenza Infection in Humans Induces Broadly Cross-Reactive and Protective Neuraminidase-Reactive Antibodies

• Type of Material: Article
• Authors: Yaoqing Chen, University of Chicago; Teddy John Wohlbold, Icahn School of Medicine; Nai-Ying Zheng, University of Chicago; Min Huang, University of Chicago; Yunping Huang, University of Chicago; Karlynn E. Neu, University of Chicago; Jiwon Lee, University of Texas, Austin; Hongquan Wan, Food and Drug Administration; Karla Thatcher Rojas, University of Chicago; Ericka Kirkpatrick, Icahn School of Medicine; Carole Henry, University of Chicago; Anna-Karin E. Palm, University of Chicago; Christopher T. Stamper, University of Chicago; Linda Yu-Ling Lan, University of Chicago; David J. Topham, University of Rochester; John Treanor, University of Rochester; Jens Wrammert, Emory University; Rafi Ahmed, Emory University; Maryna C. Eichelberger, Food and Drug Administration; George Georgiou, University of Texas Austin; Florian Krammer, Icahn School of Medicine; Patrick C. Wilson, University of Chicago
• Language: English
• Date: 2018-04-05
• Publisher: IOS Press
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2018 Elsevier Inc.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.cell.2018.03.030
• Title of Journal or Parent Work: Analytical Cellular Pathology / Cellular Oncology
• ISSN: 1570-5870
• Volume: 173
• Issue: 2
• Start Page: 417
• End Page: +
• Grant/Funding Information: This project was funded in parts from the National Institute of Allergy and Infectious Disease; National Institutes of Health grant numbers U19AI082724 (PCW), U19AI109946 (PCW), U19AI057266 (PCW), U19AI109946 (FK); and the NIAID Centers of Excellence for Influenza Research and Surveillance (CEIRS, HHSN272201400005C, PCW, DJT and JT, and HHSN272201400008C, FK); a CEIRS training grant to (TJW); and by the FDA (JW and MCE).
• Keywords: HEMAGGLUTININ; ANTIGEN; HUMAN MONOCLONAL-ANTIBODIES; VIRUS SURFACE GLYCOPROTEINS; Cell Biology; Biochemistry & Molecular Biology; VIRAL NEURAMINIDASE; UNITED-STATES; PANDEMIC H1N1; Science & Technology; IN-VIVO; EPITOPES; Life Sciences & Biomedicine; B-CELLS
• Research Categories: Biology, Molecular; Biology, Cell; Health Sciences, Immunology

Abstract

Antibodies to the hemagglutinin (HA) and neuraminidase (NA) glycoproteins are the major mediators of protection against influenza virus infection. Here, we report that current influenza vaccines poorly display key NA epitopes and rarely induce NA-reactive B cells. Conversely, influenza virus infection induces NA-reactive B cells at a frequency that approaches (H1N1) or exceeds (H3N2) that of HA-reactive B cells. NA-reactive antibodies display broad binding activity spanning the entire history of influenza A virus circulation in humans, including the original pandemic strains of both H1N1 and H3N2 subtypes. The antibodies robustly inhibit the enzymatic activity of NA, including oseltamivir-resistant variants, and provide robust prophylactic protection, including against avian H5N1 viruses, in vivo. When used therapeutically, NA-reactive antibodies protected mice from lethal influenza virus challenge even 48 hr post infection. These findings strongly suggest that influenza vaccines should be optimized to improve targeting of NA for durable and broad protection against divergent influenza strains. Current influenza vaccines predominantly produce antibodies targeting the viral hemagglutinin (HA). However, during natural infection, the body also produces antibodies targeting the viral neuraminidase (NA). These NA antibodies can provide robust and broad protection and could potentially be elicited prophylactically or via new vaccine strategies or used therapeutically.