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-Structure paper
タイトル | Hemagglutinin-stem nanoparticles generate heterosubtypic influenza protection. |
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ジャーナル・号・ページ | Nat Med, Vol. 21, Issue 9, Page 1065-1070, Year 2015 |
掲載日 | 2015年8月24日 |
著者 | Hadi M Yassine / Jeffrey C Boyington / Patrick M McTamney / Chih-Jen Wei / Masaru Kanekiyo / Wing-Pui Kong / John R Gallagher / Lingshu Wang / Yi Zhang / M Gordon Joyce / Daniel Lingwood / Syed M Moin / Hanne Andersen / Yoshinobu Okuno / Srinivas S Rao / Audray K Harris / Peter D Kwong / John R Mascola / Gary J Nabel / Barney S Graham / |
PubMed 要旨 | The antibody response to influenza is primarily focused on the head region of the hemagglutinin (HA) glycoprotein, which in turn undergoes antigenic drift, thus necessitating annual updates of ...The antibody response to influenza is primarily focused on the head region of the hemagglutinin (HA) glycoprotein, which in turn undergoes antigenic drift, thus necessitating annual updates of influenza vaccines. In contrast, the immunogenically subdominant stem region of HA is highly conserved and recognized by antibodies capable of binding multiple HA subtypes. Here we report the structure-based development of an H1 HA stem-only immunogen that confers heterosubtypic protection in mice and ferrets. Six iterative cycles of structure-based design (Gen1-Gen6) yielded successive H1 HA stabilized-stem (HA-SS) immunogens that lack the immunodominant head domain. Antigenic characterization, determination of two HA-SS crystal structures in complex with stem-specific monoclonal antibodies and cryo-electron microscopy analysis of HA-SS on ferritin nanoparticles (H1-SS-np) confirmed the preservation of key structural elements. Vaccination of mice and ferrets with H1-SS-np elicited broadly cross-reactive antibodies that completely protected mice and partially protected ferrets against lethal heterosubtypic H5N1 influenza virus challenge despite the absence of detectable H5N1 neutralizing activity in vitro. Passive transfer of immunoglobulin from H1-SS-np-immunized mice to naive mice conferred protection against H5N1 challenge, indicating that vaccine-elicited HA stem-specific antibodies can protect against diverse group 1 influenza strains. |
リンク | Nat Med / PubMed:26301691 |
手法 | EM (単粒子) / X線回折 |
解像度 | 3.188 - 16.0 Å |
構造データ | EMDB-6332: PDB-5c0r: PDB-5c0s: |
化合物 | ChemComp-NAG: ChemComp-HOH: |
由来 |
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キーワード | VIRAL PROTEIN/IMMUNE SYSTEM (ウイルス性) / Hemagglutinin (ヘマグルチニン) / immunogen (免疫原) / trimer / complex / VIRAL PROTEIN-IMMUNE SYSTEM complex (ウイルス性) |