Science: A stable trimeric influenza hemagglutinin stem as a broadly protective immunogen

[tetano]

Published Online August 24 2015
< Science Express Index

Science DOI: 10.1126/science.aac7263

• Research Article

[h=1]A stable trimeric influenza hemagglutinin stem as a broadly protective immunogen[/h]

• Antonietta Impagliazzo[SUP]1[/SUP],*,?,
• Fin Milder[SUP]1[/SUP],?,?,
• Harmjan Kuipers[SUP]1[/SUP],?,?,
• Michelle Wagner[SUP]2[/SUP],?,
• Xueyong Zhu[SUP]3[/SUP],?,
• Ryan M. B. Hoffman[SUP]3[/SUP],?,
• Ruud van Meersbergen[SUP]1[/SUP],?,
• Jeroen Huizingh[SUP]1[/SUP],?,
• Patrick Wanningen[SUP]1[/SUP],?,
• Johan Verspuij[SUP]1[/SUP],?,
• Martijn de Man[SUP]1[/SUP],?,
• Zhaoqing Ding[SUP]2[/SUP],
• Adrian Apetri[SUP]1[/SUP],?,
• Başak K?krer[SUP]1[/SUP],?,
• Eveline Sneekes-Vriese[SUP]1[/SUP],
• Danuta Tomkiewicz[SUP]1[/SUP],?,
• Nick S. Laursen[SUP]3[/SUP],?,
• Peter S. Lee[SUP]3[/SUP],
• Anna Zakrzewska[SUP]1[/SUP],?,
• Liesbeth Dekking[SUP]1[/SUP],?,
• Jeroen Tolboom[SUP]1[/SUP],?,
• Lisanne Tettero[SUP]1[/SUP],?,
• Sander van Meerten[SUP]1[/SUP],?,
• Wenli Yu[SUP]3[/SUP],
• Wouter Koudstaal[SUP]1[/SUP],?,
• Jaap Goudsmit[SUP]1[/SUP],?,
• Andrew B. Ward[SUP]3[/SUP],
• Wim Meijberg[SUP]1[/SUP],?,
• Ian A. Wilson[SUP]3[/SUP],*,
• Katarina Rado?ević[SUP]1[/SUP],#

• [SUP]1[/SUP]Crucell Vaccine Institute, Janssen Center of Excellence for Immunoprophylaxis, Archimedesweg 4-6, 2301 CA Leiden, Netherlands.
• [SUP]2[/SUP]Crucell Vaccine Institute, Janssen Center of Excellence for Immunoprophylaxis, 3210 Merryfield Row, San Diego, CA 92121, USA.
• [SUP]3[/SUP]Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.

• ↵*Corresponding author. E-mail: aimpagli{at}its.jnj.com (A.I.); wilson{at}scripps.edu (I.A.W.)

• ↵? These authors contributed equally to this work.

• ↵? Present address: Janssen Prevention Center, Janssen Pharmaceutical Companies of Johnson & Johnson, Archimedesweg 4-6, 2301 CA Leiden, Netherlands.
• ↵? Present address: Infectious Diseases and Vaccines Therapeutic Area, Janssen Research and Development, Janssen Pharmaceutical Companies of Johnson & Johnson, Archimedesweg 4-6, 2301 CA Leiden, Netherlands.
• ||Present address: Janssen Prevention Center, Janssen Pharmaceutical Companies of Johnson & Johnson, 3210 Merryfield Row, San Diego, CA 92121, USA.
• ↵? Present address: Department of Molecular Biology and Genetics, Aarhus University, Aarhus 8000, Denmark.
• ↵# Present address: Global Biotherapeutics, Sanofi, 94400 Vitry-sur-Seine, France.

[h=2]Abstract[/h] 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 full-length HA, completely protects mice in lethal heterologous and heterosubtypic challenge models, and reduces fever following sublethal challenge in cynomolgus monkeys. Antibodies elicited by this mini-HA in mice and nonhuman primates bind a wide range of HAs, compete with human bnAbs for HA stem binding, neutralize H5N1 viruses, and mediate antibody-dependent effector activity. These results provide proof-of-concept for design of HA stem mimics that elicit bnAbs against influenza A group 1 viruses.



http://www.sciencemag.org/content/early/2015/08/24/science.aac7263