title: A stable trimeric influenza hemagglutinin stem as a broadly protective immunogen.
abstract: 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.
authors: Crucell Vaccine Institute, Janssen Center of Excellence for Immunoprophylaxis, Archimedesweg 4-6, 2301 CA Leiden, Netherlands. aimpagli@its.jnj.com wilson@scripps.edu.
authors: Antonietta
authors: A
authors: Impagliazzo
authors: Crucell Vaccine Institute, Janssen Center of Excellence for Immunoprophylaxis, Archimedesweg 4-6, 2301 CA Leiden, Netherlands.
authors: Fin
authors: F
authors: Milder
authors: Crucell Vaccine Institute, Janssen Center of Excellence for Immunoprophylaxis, Archimedesweg 4-6, 2301 CA Leiden, Netherlands.
authors: Harmjan
authors: H
authors: Kuipers
authors: Crucell Vaccine Institute, Janssen Center of Excellence for Immunoprophylaxis, 3210 Merryfield Row, San Diego, CA 92121, USA.
authors: Michelle V
authors: MV
authors: Wagner
authors: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors: Xueyong
authors: X
authors: Zhu
authors: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors: Ryan M B
authors: RM
authors: Hoffman
authors: Crucell Vaccine Institute, Janssen Center of Excellence for Immunoprophylaxis, Archimedesweg 4-6, 2301 CA Leiden, Netherlands.
authors: Ruud
authors: R
authors: van Meersbergen
authors: Crucell Vaccine Institute, Janssen Center of Excellence for Immunoprophylaxis, Archimedesweg 4-6, 2301 CA Leiden, Netherlands.
authors: Jeroen
authors: J
authors: Huizingh
authors: Crucell Vaccine Institute, Janssen Center of Excellence for Immunoprophylaxis, Archimedesweg 4-6, 2301 CA Leiden, Netherlands.
authors: Patrick
authors: P
authors: Wanningen
authors: Crucell Vaccine Institute, Janssen Center of Excellence for Immunoprophylaxis, Archimedesweg 4-6, 2301 CA Leiden, Netherlands.
authors: Johan
authors: J
authors: Verspuij
authors: Crucell Vaccine Institute, Janssen Center of Excellence for Immunoprophylaxis, Archimedesweg 4-6, 2301 CA Leiden, Netherlands.
authors: Martijn
authors: M
authors: de Man
authors: Crucell Vaccine Institute, Janssen Center of Excellence for Immunoprophylaxis, 3210 Merryfield Row, San Diego, CA 92121, USA.
authors: Zhaoqing
authors: Z
authors: Ding
authors: Crucell Vaccine Institute, Janssen Center of Excellence for Immunoprophylaxis, Archimedesweg 4-6, 2301 CA Leiden, Netherlands.
authors: Adrian
authors: A
authors: Apetri
authors: Crucell Vaccine Institute, Janssen Center of Excellence for Immunoprophylaxis, Archimedesweg 4-6, 2301 CA Leiden, Netherlands.
authors: Başak
authors: B
authors: Kükrer
authors: Crucell Vaccine Institute, Janssen Center of Excellence for Immunoprophylaxis, Archimedesweg 4-6, 2301 CA Leiden, Netherlands.
authors: Eveline
authors: E
authors: Sneekes-Vriese
authors: Crucell Vaccine Institute, Janssen Center of Excellence for Immunoprophylaxis, Archimedesweg 4-6, 2301 CA Leiden, Netherlands.
authors: Danuta
authors: D
authors: Tomkiewicz
authors: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors: Nick S
authors: NS
authors: Laursen
authors: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors: Peter S
authors: PS
authors: Lee
authors: Crucell Vaccine Institute, Janssen Center of Excellence for Immunoprophylaxis, Archimedesweg 4-6, 2301 CA Leiden, Netherlands.
authors: Anna
authors: A
authors: Zakrzewska
authors: Crucell Vaccine Institute, Janssen Center of Excellence for Immunoprophylaxis, Archimedesweg 4-6, 2301 CA Leiden, Netherlands.
authors: Liesbeth
authors: L
authors: Dekking
authors: Crucell Vaccine Institute, Janssen Center of Excellence for Immunoprophylaxis, Archimedesweg 4-6, 2301 CA Leiden, Netherlands.
authors: Jeroen
authors: J
authors: Tolboom
authors: Crucell Vaccine Institute, Janssen Center of Excellence for Immunoprophylaxis, Archimedesweg 4-6, 2301 CA Leiden, Netherlands.
authors: Lisanne
authors: L
authors: Tettero
authors: Crucell Vaccine Institute, Janssen Center of Excellence for Immunoprophylaxis, Archimedesweg 4-6, 2301 CA Leiden, Netherlands.
authors: Sander
authors: S
authors: van Meerten
authors: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors: Wenli
authors: W
authors: Yu
authors: Crucell Vaccine Institute, Janssen Center of Excellence for Immunoprophylaxis, Archimedesweg 4-6, 2301 CA Leiden, Netherlands.
authors: Wouter
authors: W
authors: Koudstaal
authors: Crucell Vaccine Institute, Janssen Center of Excellence for Immunoprophylaxis, Archimedesweg 4-6, 2301 CA Leiden, Netherlands.
authors: Jaap
authors: J
authors: Goudsmit
authors: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors: Andrew B
authors: AB
authors: Ward
authors: Crucell Vaccine Institute, Janssen Center of Excellence for Immunoprophylaxis, Archimedesweg 4-6, 2301 CA Leiden, Netherlands.
authors: Wim
authors: W
authors: Meijberg
authors: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA. aimpagli@its.jnj.com wilson@scripps.edu.
authors: Ian A
authors: IA
authors: Wilson
authors: Crucell Vaccine Institute, Janssen Center of Excellence for Immunoprophylaxis, Archimedesweg 4-6, 2301 CA Leiden, Netherlands.
authors: Katarina
authors: K
authors: Radošević
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D000914:Antibodies, Viral / Q000276:immunology; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000737:chemistry* / Q000276:immunology*; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology*; D053124:Influenza A Virus, H5N1 Subtype / Q000276:immunology*; D007252:Influenza Vaccines / Q000276:immunology*; D007251:Influenza, Human / Q000517:prevention & control*; D051379:Mice; D055503:Protein Multimerization; D017433:Protein Structure, Secondary
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; C543345:H1N1 virus hemagglutinin; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D007252:Influenza Vaccines