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

Crucell Vaccine Institute
The Scripps Research Institute

Onderzoeksoutput: Article › Academic › peer review

Samenvatting

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.

Originele taal-2	English
Pagina's (van-tot)	1301-6
Aantal pagina's	6
Tijdschrift	Science
Volume	349
Nummer van het tijdschrift	6254
DOI's	https://doi.org/10.1126/science.aac7263
Status	Published - 24 aug. 2015
Extern gepubliceerd	Ja

Keywords

dieren
antilichamen, neutraliserend/immunologie
antilichamen, virale/immunologie
hemagglutinineglycoproteïnen, influenzavirus/chemie
mensen
influenza A-virus, H1N1-subtype/immunologie
influenza A-virus, H5N1-subtype/immunologie
griepvaccins/immunologie
griep, mensen/preventie & controle
muizen
multimerisatie van eiwitten
eiwitstructuur, secundair

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10.1126/science.aac7263

Citeer dit

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), 1301-6. https://doi.org/10.1126/science.aac7263

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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.",

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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",

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, nr. 6254, blz. 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

JF - Science

IS - 6254

ER -

A stable trimeric influenza hemagglutinin stem as a broadly protective immunogen

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Keywords

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