Exposure of an occluded hemagglutinin epitope drives selection of a class of cross-protective influenza antibodies

Yu Adachi, Keisuke Tonouchi, Arnone Nithichanon, Masayuki Kuraoka, Akiko Watanabe, Ryo Shinnakasu, Hideki Asanuma, Akira Ainai, Yusuke Ohmi, Takuya Yamamoto, Ken J. Ishii, Hideki Hasegawa, Haruko Takeyama, Ganjana Lertmemongkolchai, Tomohiro Kurosaki, Manabu Ato, Garnett Kelsoe and Yoshimasa Takahashi ()
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Yu Adachi: National Institute of Infectious Diseases
Keisuke Tonouchi: National Institute of Infectious Diseases
Arnone Nithichanon: National Institute of Infectious Diseases
Masayuki Kuraoka: Duke University
Akiko Watanabe: Duke University
Ryo Shinnakasu: Osaka University
Hideki Asanuma: National Institute of Infectious Diseases
Akira Ainai: National Institute of Infectious Diseases
Yusuke Ohmi: Chubu University College of Life and Health Sciences
Takuya Yamamoto: National Institutes of Biomedical Innovation, Health and Nutrition
Ken J. Ishii: National Institutes of Biomedical Innovation, Health and Nutrition
Hideki Hasegawa: National Institute of Infectious Diseases
Haruko Takeyama: Waseda University
Ganjana Lertmemongkolchai: Khon Kaen University
Tomohiro Kurosaki: Osaka University
Manabu Ato: National Institute of Infectious Diseases
Garnett Kelsoe: Duke University
Yoshimasa Takahashi: National Institute of Infectious Diseases

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-11821-6

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