A stable trimeric influenza hemagglutinin stem as a broadly protective immunogen

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

Research output: Contribution to journalArticleAcademicpeer-review


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
Pages (from-to)1301-6
Number of pages6
JournalScience (New York, N.Y.)
Issue number6254
Publication statusPublished - 24 Aug 2015
Externally publishedYes


  • animals
  • antibodies, neutralizing/immunology
  • antibodies, viral/immunology
  • hemagglutinin glycoproteins, influenza virus/chemistry
  • humans
  • influenza A virus, H1N1 subtype/immunology
  • influenza A virus, H5N1 subtype/immunology
  • influenza vaccines/immunology
  • influenza, human/prevention & control
  • mice
  • protein multimerization
  • protein structure, secondary


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