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 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 journal › Article › Academic › peer-review

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)	1301-6
Number of pages	6
Journal	Science (New York, N.Y.)
Volume	349
Issue number	6254
DOIs	https://doi.org/10.1126/science.aac7263
Publication status	Published - 24 Aug 2015
Externally published	Yes

Keywords

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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10.1126/science.aac7263

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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 (New York, N.Y.), 349(6254), 1301-6. https://doi.org/10.1126/science.aac7263

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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.",

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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}",

note = "Copyright {\textcopyright} 2015, American Association for the Advancement of Science.",

year = "2015",

month = aug,

day = "24",

doi = "10.1126/science.aac7263",

language = "English",

volume = "349",

pages = "1301--6",

journal = "Science (New York, N.Y.)",

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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 (New York, N.Y.), vol. 349, no. 6254, pp. 1301-6. 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 - 2015/8/24

Y1 - 2015/8/24

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.

KW - animals

KW - antibodies, neutralizing/immunology

KW - antibodies, viral/immunology

KW - hemagglutinin glycoproteins, influenza virus/chemistry

KW - humans

KW - influenza A virus, H1N1 subtype/immunology

KW - influenza A virus, H5N1 subtype/immunology

KW - influenza vaccines/immunology

KW - influenza, human/prevention & control

KW - mice

KW - protein multimerization

KW - protein structure, secondary

KW - dieren

KW - antilichamen, neutraliserend/immunologie

KW - antilichamen, virale/immunologie

KW - hemagglutinineglycoproteïnen, influenzavirus/chemie

KW - mensen

KW - influenza A-virus, H1N1-subtype/immunologie

KW - influenza A-virus, H5N1-subtype/immunologie

KW - griepvaccins/immunologie

KW - griep, mensen/preventie & controle

KW - muizen

KW - multimerisatie van eiwitten

KW - eiwitstructuur, secundair

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 (New York, N.Y.)

JF - Science (New York, N.Y.)

IS - 6254

ER -

A stable trimeric influenza hemagglutinin stem as a broadly protective immunogen

Abstract

Keywords

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