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Nat Commun. 2019 Aug 28;10(1):3883. doi: 10.1038/s41467-019-11821-6.
Exposure of an occluded hemagglutinin epitope drives selection of a class of cross-protective influenza antibodies.
Adachi Y1, Tonouchi K1,2, Nithichanon A1,3, Kuraoka M4, Watanabe A4, Shinnakasu R5, Asanuma H6,7, Ainai A7, Ohmi Y8, Yamamoto T9, Ishii KJ10,11, Hasegawa H6,7, Takeyama H2, Lertmemongkolchai G3, Kurosaki T5,12, Ato M13, Kelsoe G4,14, Takahashi Y15.
Author information
1 Department of Immunology, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku, Tokyo, 162-8640, Japan. 2 Department of Life Science and Medical Bioscience, Waseda University, 2-2 Wakamatsucho, Shinjuku, Tokyo, 162-8480, Japan. 3 Center for Research and Development of Medical Diagnostic Laboratories (CMDL), Faculty of Associated Medical Sciences, Khon Kaen University, 123 Mittraphap Road, Khon Kaen, 40002, Thailand. 4 Department of Immunology, Duke University, Durham, NC, 27710, USA. 5 Laboratory of Lymphocyte Differentiation, WPI Immunology Frontier Research Center and Graduate School of Frontier Biosciences, Osaka University, 3-1 Yamadaoka, Suita, Osaka, 565-0871, Japan. 6 Influenza Virus Research Center, National Institute of Infectious Diseases, 4-7-1 Gakuen, Musashimurayama, Tokyo, 208-0011, Japan. 7 Department of Pathology, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku, Tokyo, 162-8640, Japan. 8 Department of Clinical Engineering, Chubu University College of Life and Health Sciences, 1200 Matsumoto, Kasugai, 487-8501, Aichi, Japan. 9 Laboratory of Immunosenescence, Center for Vaccine and Adjuvant Research, National Institutes of Biomedical Innovation, Health and Nutrition, 7-6-8 Saitoasagi, Ibaraki, Osaka, 567-0085, Japan. 10 Center for Vaccine and Adjuvant Research, National Institutes of Biomedical Innovation, Health and Nutrition, 7-6-8 Saitoasagi, Ibaraki, Osaka, 567-0085, Japan. 11 Division of Vaccine Science, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shiroganedai, Minato, Tokyo, 108-8639, Japan. 12 Laboratory for Lymphocyte Differentiation, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehirocho, Tsurumi, Yokohama, Kanagawa, 230-0045, Japan. 13 Department of Mycobacteriology, National Institute of Infectious Diseases, 4-2-1 Aobacho, Higashimurayama, Tokyo, 189-0002, Japan. 14 Human Vaccine Institute, Duke University, Durham, NC, 27710, USA. 15 Department of Immunology, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku, Tokyo, 162-8640, Japan. ytakahas@niid.go.jp.
Abstract
Germinal center (GC) B cells at viral replication sites acquire specificity to poorly immunogenic but conserved influenza hemagglutinin (HA) epitopes. Here, high-throughput epitope mapping of local GC B cells is used to identify conserved HA epitope selecting cross-reactive antibodies that mediate heterosubtypic protection. A distinct feature of this epitope is an occlusion in the naive trimeric HA structure that is exposed in the post-fusion HA structure to occur under low pH conditions during viral replication. Importantly, systemic immunization by the post-fusion HA antigen results in GC B cells targeting the occluded epitope, and induces a class of protective antibodies that have cross-group specificity and afford protection independent of virus neutralization activity. Furthermore, this class of broadly protective antibodies develops at late time points and persists. Our results identify a class of cross-protective antibodies that are selected at the viral replication site, and provide insights into vaccine strategies using the occluded epitope.
PMID: 31462639 DOI: 10.1038/s41467-019-11821-6
Exposure of an occluded hemagglutinin epitope drives selection of a class of cross-protective influenza antibodies.
Adachi Y1, Tonouchi K1,2, Nithichanon A1,3, Kuraoka M4, Watanabe A4, Shinnakasu R5, Asanuma H6,7, Ainai A7, Ohmi Y8, Yamamoto T9, Ishii KJ10,11, Hasegawa H6,7, Takeyama H2, Lertmemongkolchai G3, Kurosaki T5,12, Ato M13, Kelsoe G4,14, Takahashi Y15.
Author information
1 Department of Immunology, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku, Tokyo, 162-8640, Japan. 2 Department of Life Science and Medical Bioscience, Waseda University, 2-2 Wakamatsucho, Shinjuku, Tokyo, 162-8480, Japan. 3 Center for Research and Development of Medical Diagnostic Laboratories (CMDL), Faculty of Associated Medical Sciences, Khon Kaen University, 123 Mittraphap Road, Khon Kaen, 40002, Thailand. 4 Department of Immunology, Duke University, Durham, NC, 27710, USA. 5 Laboratory of Lymphocyte Differentiation, WPI Immunology Frontier Research Center and Graduate School of Frontier Biosciences, Osaka University, 3-1 Yamadaoka, Suita, Osaka, 565-0871, Japan. 6 Influenza Virus Research Center, National Institute of Infectious Diseases, 4-7-1 Gakuen, Musashimurayama, Tokyo, 208-0011, Japan. 7 Department of Pathology, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku, Tokyo, 162-8640, Japan. 8 Department of Clinical Engineering, Chubu University College of Life and Health Sciences, 1200 Matsumoto, Kasugai, 487-8501, Aichi, Japan. 9 Laboratory of Immunosenescence, Center for Vaccine and Adjuvant Research, National Institutes of Biomedical Innovation, Health and Nutrition, 7-6-8 Saitoasagi, Ibaraki, Osaka, 567-0085, Japan. 10 Center for Vaccine and Adjuvant Research, National Institutes of Biomedical Innovation, Health and Nutrition, 7-6-8 Saitoasagi, Ibaraki, Osaka, 567-0085, Japan. 11 Division of Vaccine Science, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shiroganedai, Minato, Tokyo, 108-8639, Japan. 12 Laboratory for Lymphocyte Differentiation, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehirocho, Tsurumi, Yokohama, Kanagawa, 230-0045, Japan. 13 Department of Mycobacteriology, National Institute of Infectious Diseases, 4-2-1 Aobacho, Higashimurayama, Tokyo, 189-0002, Japan. 14 Human Vaccine Institute, Duke University, Durham, NC, 27710, USA. 15 Department of Immunology, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku, Tokyo, 162-8640, Japan. ytakahas@niid.go.jp.
Abstract
Germinal center (GC) B cells at viral replication sites acquire specificity to poorly immunogenic but conserved influenza hemagglutinin (HA) epitopes. Here, high-throughput epitope mapping of local GC B cells is used to identify conserved HA epitope selecting cross-reactive antibodies that mediate heterosubtypic protection. A distinct feature of this epitope is an occlusion in the naive trimeric HA structure that is exposed in the post-fusion HA structure to occur under low pH conditions during viral replication. Importantly, systemic immunization by the post-fusion HA antigen results in GC B cells targeting the occluded epitope, and induces a class of protective antibodies that have cross-group specificity and afford protection independent of virus neutralization activity. Furthermore, this class of broadly protective antibodies develops at late time points and persists. Our results identify a class of cross-protective antibodies that are selected at the viral replication site, and provide insights into vaccine strategies using the occluded epitope.
PMID: 31462639 DOI: 10.1038/s41467-019-11821-6