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. 2018 Feb;76(2):177-185.
doi: 10.1016/j.jinf.2017.12.004. Epub 2017 Dec 14.

Human protective monoclonal antibodies against the HA stem of group 2 HAs derived from an H3N2 virus-infected human

Seiya Yamayoshi  1 , Mutsumi Ito  1 , Ryuta Uraki  1 , Tadahiro Sasaki  2 , Kazuyoshi Ikuta  2 , Yoshihiro Kawaoka  3
Affiliations

Human protective monoclonal antibodies against the HA stem of group 2 HAs derived from an H3N2 virus-infected human

Seiya Yamayoshi et al. J Infect. 2018 Feb.

Abstract

Objectives: Broadly reactive human monoclonal antibodies against the HA stem of influenza A virus are being developed as therapeutic agents as well as to understand the epitopes that are essential for a universal influenza virus vaccine.

Methods: We isolated and characterized two hetero-reactive human monoclonal antibodies from an H3N2 virus-infected human.

Results: These antibodies, which are predominantly bound to the HA stem of group 2 HAs, used IGHV3-66 and IGHV4-38-2 germline genes, respectively. They possessed in vitro neutralizing ability, and in vivo protective efficacy against lethal infection with H3N2 or H7N9 virus. Escape mutations revealed that one of the protective antibodies recognized the α-helix A of HA2, and the other recognized the C-terminal portion of the fusion peptide and the β-sheet that precedes the α-helix A of HA2.

Conclusions: Of many human protective monoclonal antibodies against the HA stem, two human protective monoclonal antibodies were isolated in this study that predominantly recognize epitopes on the HA stem of group 2 and use unique IGHV3-66 and IGHV4-38-2 germline genes.

Keywords: Group 2; HA stem; Human monoclonal antibody; Influenza A virus.

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Conflict of interest statement

Conflicts of interest

Y.K. has received speaker’s honoraria from Toyama Chemical and Astellas Inc., has received grant support from Chugai Pharmaceuticals, Daiichi Sankyo Pharmaceutical, Toyama Chemical, Tauns Laboratories, Inc., Otsuka Pharmaceutical Co., Ltd., and Denka Seiken Co., Ltd., and is a co-founder of FluGen.

Figures

Figure 1.
Figure 1.. Epitope analysis on H3-HA.
(A) Mutations found in H3-HA after passages of Perth/16 in the presence of 1417infE21 (cyan) or 1417infC10 (green). Perth/16 was passaged in the presence of various concentrations of 1417infE21 or 1417infC10 in MDCK cells. After 6–16 passages, the HA sequence of the escape mutant viruses was analyzed and the identified escape mutations were mapped onto the 3D structure of the H3-HA trimer by using the molecular graphics system PyMOL. Two independent experiments were performed. Mutations are shown with H3 numbering. (B) Competitive binding of 1417infE21 or 1417infC10 to H3-HA. Additional binding of the indicated human mAbs to the immobilized H3-HA saturated with 1417infE21, 1417infC10, CR8020, or F008–090, was measured by means of bio-layer interferometry.
Figure 2.
Figure 2.. In vivo protective efficacy in mice.
Four mice per group were intraperitoneally injected with PBS or the indicated antibodies at 30 mg/kg. One day later, the mice were challenged with 10 MLD50 of MA-CA04 (H1N1pdm09), MA-Aichi (H3N2), VN1203 (H5N1), or PA-11Mut (H7N9) virus. Body weight and survival were monitored daily for 14 days. 1429C6/3–3, which recognizes influenza B virus HA, and PBS served as negative controls.
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