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 Dekking; Jeroen Tolboom; Lisanne Tettero; Sander van Meerten; Wenli Yu; Wouter Koudstaal; Jaap Goudsmit; Andrew B. Ward; Wim Meijberg; Ian A. Wilson; Katarina Radošević

doi:10.1126/science.aac7263

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 Dekking

Jeroen Tolboom, Lisanne Tettero, Sander van Meerten, Wenli Yu, Wouter Koudstaal, Jaap Goudsmit, Andrew B. Ward, Wim Meijberg, Ian A. Wilson, Katarina Radošević

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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

Original language	English
Pages (from-to)	1301-1306
Journal	Science
Volume	349
Issue number	6254
DOIs	https://doi.org/10.1126/science.aac7263
Publication status	Published - 2015

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SDG 3 Good Health and Well-being

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Impagliazzo, A., Milder, F., Kuipers, H., Wagner, M. V., Zhu, X., Hoffman, R. M. B., van Meersbergen, R., Huizingh, J., Wanningen, P., Verspuij, J., de Man, M., Ding, Z., Apetri, A., Kükrer, B., Sneekes-Vriese, E., Tomkiewicz, D., Laursen, N. S., Lee, P. S., Zakrzewska, A., ... Radošević, K. (2015). A stable trimeric influenza hemagglutinin stem as a broadly protective immunogen. Science, 349(6254), 1301-1306. https://doi.org/10.1126/science.aac7263

@article{1f7f7b02485f4efda03ecd4a91cd26ac,

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",

author = "Antonietta Impagliazzo and Fin Milder and Harmjan Kuipers and Wagner, \{Michelle V.\} and Xueyong Zhu and Hoffman, \{Ryan M. B.\} and \{van Meersbergen\}, Ruud and Jeroen Huizingh and Patrick Wanningen and Johan Verspuij and \{de Man\}, Martijn and Zhaoqing Ding and Adrian Apetri and Ba{\c s}ak K{\"u}krer and Eveline Sneekes-Vriese and Danuta Tomkiewicz and Laursen, \{Nick S.\} and Lee, \{Peter S.\} and Anna Zakrzewska and Liesbeth Dekking and Jeroen Tolboom and Lisanne Tettero and \{van Meerten\}, Sander and Wenli Yu and Wouter Koudstaal and Jaap Goudsmit and Ward, \{Andrew B.\} and Wim Meijberg and Wilson, \{Ian A.\} and Katarina Rado{\v s}evi{\'c}",

year = "2015",

doi = "10.1126/science.aac7263",

language = "English",

volume = "349",

pages = "1301--1306",

journal = "Science",

issn = "0036-8075",

publisher = "American Association for the Advancement of Science",

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Impagliazzo, A, Milder, F, Kuipers, H, Wagner, MV, Zhu, X, Hoffman, RMB, van Meersbergen, R, Huizingh, J, Wanningen, P, Verspuij, J, de Man, M, Ding, Z, Apetri, A, Kükrer, B, Sneekes-Vriese, E, Tomkiewicz, D, Laursen, NS, Lee, PS, Zakrzewska, A, Dekking, L, Tolboom, J, Tettero, L, van Meerten, S, Yu, W, Koudstaal, W, Goudsmit, J, Ward, AB, Meijberg, W, Wilson, IA & Radošević, K 2015, 'A stable trimeric influenza hemagglutinin stem as a broadly protective immunogen', Science, vol. 349, no. 6254, pp. 1301-1306. https://doi.org/10.1126/science.aac7263

TY - JOUR

T1 - A stable trimeric influenza hemagglutinin stem as a broadly protective immunogen

AU - Impagliazzo, Antonietta

AU - Milder, Fin

AU - Kuipers, Harmjan

AU - Wagner, Michelle V.

AU - Zhu, Xueyong

AU - Hoffman, Ryan M. B.

AU - van Meersbergen, Ruud

AU - Huizingh, Jeroen

AU - Wanningen, Patrick

AU - Verspuij, Johan

AU - de Man, Martijn

AU - Ding, Zhaoqing

AU - Apetri, Adrian

AU - Kükrer, Başak

AU - Sneekes-Vriese, Eveline

AU - Tomkiewicz, Danuta

AU - Laursen, Nick S.

AU - Lee, Peter S.

AU - Zakrzewska, Anna

AU - Dekking, Liesbeth

AU - Tolboom, Jeroen

AU - Tettero, Lisanne

AU - van Meerten, Sander

AU - Yu, Wenli

AU - Koudstaal, Wouter

AU - Goudsmit, Jaap

AU - Ward, Andrew B.

AU - Meijberg, Wim

AU - Wilson, Ian A.

AU - Radošević, Katarina

PY - 2015

Y1 - 2015

N2 - 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

AB - 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

U2 - 10.1126/science.aac7263

DO - 10.1126/science.aac7263

M3 - Article

C2 - 26303961

SN - 0036-8075

VL - 349

SP - 1301

EP - 1306

JO - Science

JF - Science

IS - 6254

ER -

A stable trimeric influenza hemagglutinin stem as a broadly protective immunogen

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