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A stable trimeric influenza hemagglutinin stem as a broadly protective immunogen

by Hoffman, Ryan M. B. , Kükrer, Başak , Lee, Peter S. , Laursen, Nick S. , Wanningen, Patrick , Dekking, Liesbeth , Tolboom, Jeroen , Tomkiewicz, Danuta , Meijberg, Wim , Zhu, Xueyong , Tettero, Lisanne , Yu, Wenli , Verspuij, Johan , van Meerten, Sander , Radošević, Katarina , Milder, Fin , Huizingh, Jeroen , Wilson, Ian A. , Ding, Zhaoqing , Apetri, Adrian , van Meersbergen, Ruud , de Man, Martijn , Zakrzewska, Anna , Impagliazzo, Antonietta , Goudsmit, Jaap , Koudstaal, Wouter , Sneekes-Vriese, Eveline , Kuipers, Harmjan , Wagner, Michelle V. , Ward, Andrew B.

in Animals / Antibodies / Antibodies, Neutralizing - immunology / Antibodies, Viral - immunology / Binding / Cynomolgus / Design engineering / Hemagglutinin Glycoproteins, Influenza Virus - chemistry / Hemagglutinin Glycoproteins, Influenza Virus - immunology / Humans / Influenza / Influenza A Virus, H1N1 Subtype - immunology / Influenza A Virus, H5N1 Subtype - immunology / Influenza Vaccines - immunology / Influenza virus / Influenza, Human - prevention & control / Mice / Mutation / Orthomyxoviridae / Primates / Protein Multimerization / Protein Structure, Secondary / Proteins / RESEARCH ARTICLE / Vaccines / Viruses

2015

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A stable trimeric influenza hemagglutinin stem as a broadly protective immunogen

2015

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A stable trimeric influenza hemagglutinin stem as a broadly protective immunogen

2015

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Journal Article

A stable trimeric influenza hemagglutinin stem as a broadly protective immunogen

Hoffman, Ryan M. B.,

Kükrer, Başak,

Lee, Peter S.,

Laursen, Nick S.,

Wanningen, Patrick,

Dekking, Liesbeth,

Tolboom, Jeroen,

Tomkiewicz, Danuta,

Meijberg, Wim,

Zhu, Xueyong,

Tettero, Lisanne,

Yu, Wenli,

Verspuij, Johan,

van Meerten, Sander,

Radošević, Katarina,

Milder, Fin,

Huizingh, Jeroen,

Wilson, Ian A.,

Ding, Zhaoqing,

Apetri, Adrian,

van Meersbergen, Ruud,

de Man, Martijn,

Zakrzewska, Anna,

Impagliazzo, Antonietta,

Goudsmit, Jaap,

Koudstaal, Wouter,

Sneekes-Vriese, Eveline,

Kuipers, Harmjan,

Wagner, Michelle V.,

Ward, Andrew B.

2015

Overview

The identification of human broadly neutralizing antibodies (bnAbs) targeting the hemagglutinin (HA) stem revitalized hopes of developing a universal influenza vaccine. Using a rational design and library approach, we engineered stable HA stem antigens (\"mini-HAs\") based on an H1 subtype sequence. Our most advanced candidate exhibits structural and bnAb binding properties comparable to those of full-length HA, completely protects mice in lethal heterologous and heterosubtypic challenge models, and reduces fever after sublethal challenge in cynomolgus monkeys. Antibodies elicited by this mini-HA in mice and nonhuman primates bound a wide range of HAs, competed with human bnAbs for HA stem binding, neutralized H5N1 viruses, and mediated antibody-dependent effector activity. These results represent a proof of concept for the design of HA stem mimics that elicit bnAbs against influenza A group 1 viruses.

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Publisher

American Association for the Advancement of Science,The American Association for the Advancement of Science

Subject

Animals

/ Antibodies

/ Antibodies, Neutralizing - immunology

/ Antibodies, Viral - immunology

/ Binding

/ Cynomolgus

/ Design engineering