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Keywords influenza; neuraminidase; vaccine; virus infection; monoclonal antibody; B cell; humoral immune response; therapeutics; human immunology Highlights * Flu virus infection induces many neuraminidase (NA)-reactive B cells and antibodies * NA antibodies have broad cross-reactivity and inhibit neuraminidase enzyme activity * Current flu vaccines poorly display key NA epitopes and do not produce NA antibodies * NA-reactive antibodies offer protection against lethal flu virus infection Summary 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. Author Affiliation: (1) Department of Medicine, Section of Rheumatology, the Knapp Center for Lupus and Immunology, University of Chicago, Chicago, IL 60637, USA (2) Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA (3) The Committee on Immunology, University of Chicago, Chicago, IL 60637, USA (4) Department of Chemical Engineering, University of Texas at Austin, Austin, TX 78731, USA (5) Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USA (6) Center for Vaccine Biology & Immunology, Department of Microbiology & Immunology, University of Rochester Medical Center, Rochester, NY 14642, USA (7) Division of Infectious Disease, Department of Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA (8) Emory Vaccine Center, Department of Pediatrics, Division of Infectious Disease, Emory University School of Medicine, Atlanta, GA 30322, USA * Corresponding author Article History: Received 13 December 2017; Revised 8 March 2018; Accepted 9 March 2018 (miscellaneous) Published: April 5, 2018 (footnote)9 Lead Contact Byline: Yao-Qing Chen (1), Teddy John Wohlbold (2), Nai-Ying Zheng (1), Min Huang (1), Yunping Huang (1), Karlynn E. Neu (3), Jiwon Lee (4), Hongquan Wan (5), Karla Thatcher Rojas (1), Ericka Kirkpatrick (2), Carole Henry (1), Anna-Karin E. Palm (1), Christopher T. Stamper (3), Linda Yu-Ling Lan (3), David J. Topham (6), John Treanor (7), Jens Wrammert (8), Rafi Ahmed (8), Maryna C. Eichelberger (5), George Georgiou (4), Florian Krammer [florian.krammer@mssm.edu] (2,*), Patrick C. Wilson [wilsonp@uchicago.edu] (1,9,**)