A stable trimeric influenza hemagglutinin stem as a broadly protective immunogen

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DOI

  • Antonietta Impagliazzo, Crucell Vaccine Institute, Janssen Center of Excellence for Immunoprophylaxis, Netherlands
  • Fin Milder, Crucell Vaccine Institute, Janssen Center of Excellence for Immunoprophylaxis, Netherlands
  • Harmjan Kuipers, Crucell Vaccine Institute, Janssen Center of Excellence for Immunoprophylaxis, Netherlands
  • Michelle V Wagner, Crucell Vaccine Institute, Janssen Center of Excellence for Immunoprophylaxis, United States
  • Xueyong Zhu, Department of Integrative Structural and Computational Biology, The Scripps Research Institute, United States
  • Ryan M B Hoffman, Department of Integrative Structural and Computational Biology, The Scripps Research Institute, United States
  • Ruud van Meersbergen, Crucell Vaccine Institute, Janssen Center of Excellence for Immunoprophylaxis, Netherlands
  • Jeroen Huizingh, Crucell Vaccine Institute, Janssen Center of Excellence for Immunoprophylaxis, Netherlands
  • Patrick Wanningen, Crucell Vaccine Institute, Janssen Center of Excellence for Immunoprophylaxis, Netherlands
  • Johan Verspuij, Crucell Vaccine Institute, Janssen Center of Excellence for Immunoprophylaxis, Netherlands
  • Martijn de Man, Crucell Vaccine Institute, Janssen Center of Excellence for Immunoprophylaxis, Netherlands
  • Zhaoqing Ding, Crucell Vaccine Institute, Janssen Center of Excellence for Immunoprophylaxis, United States
  • Adrian Apetri, Crucell Vaccine Institute, Janssen Center of Excellence for Immunoprophylaxis, Netherlands
  • Başak Kükrer, Denmark
  • Eveline Sneekes-Vriese, Denmark
  • Danuta Tomkiewicz, Denmark
  • Nick S Laursen
  • Peter S Lee, Department of Integrative Structural and Computational Biology, The Scripps Research Institute, United States
  • Anna Zakrzewska, Crucell Vaccine Institute, Janssen Center of Excellence for Immunoprophylaxis, Netherlands
  • Liesbeth Dekking, Crucell Vaccine Institute, Janssen Center of Excellence for Immunoprophylaxis, Netherlands
  • Jeroen Tolboom, Crucell Vaccine Institute, Janssen Center of Excellence for Immunoprophylaxis, Netherlands
  • Lisanne Tettero, Crucell Vaccine Institute, Janssen Center of Excellence for Immunoprophylaxis, Netherlands
  • Sander van Meerten, Crucell Vaccine Institute, Janssen Center of Excellence for Immunoprophylaxis, Netherlands
  • Wenli Yu, Department of Integrative Structural and Computational Biology, The Scripps Research Institute, United States
  • Wouter Koudstaal, Crucell Vaccine Institute, Janssen Center of Excellence for Immunoprophylaxis, Netherlands
  • Jaap Goudsmit, Crucell Vaccine Institute, Janssen Center of Excellence for Immunoprophylaxis, Netherlands
  • Andrew B Ward, Crucell Vaccine Institute, Janssen Center of Excellence for Immunoprophylaxis, United States
  • Wim Meijberg, Crucell Vaccine Institute, Janssen Center of Excellence for Immunoprophylaxis, Netherlands
  • Ian A Wilson, Crucell Vaccine Institute, Janssen Center of Excellence for Immunoprophylaxis, United States
  • Katarina Radošević, Crucell Vaccine Institute, Janssen Center of Excellence for Immunoprophylaxis, Netherlands

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.

Original languageEnglish
JournalScience
Volume349
Issue6254
Pages (from-to)1301-1306
Number of pages6
ISSN0036-8075
DOIs
Publication statusPublished - 18 Sep 2015

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