Lassa virus glycoprotein nanoparticles elicit neutralizing antibody responses and protection

Philip J.M. Brouwer; Aleksandar Antanasijevic; Adam J. Ronk; Helena Müller-Kräuter; Yasunori Watanabe; Mathieu Claireaux; Hailee R. Perrett; Tom P.L. Bijl; Marloes Grobben; Jeffrey C. Umotoy; Angela I. Schriek; Judith A. Burger; Khadija Tejjani; Nicole M. Lloyd; Thijs H. Steijaert; Marlies M. van Haaren; Kwinten Sliepen; Steven W. de Taeye; Marit J. van Gils; Max Crispin; Thomas Strecker; Alexander Bukreyev; Andrew B. Ward; Rogier W. Sanders

doi:10.1016/j.chom.2022.10.018

Lassa virus glycoprotein nanoparticles elicit neutralizing antibody responses and protection

Philip J.M. Brouwer, Aleksandar Antanasijevic, Adam J. Ronk, Helena Müller-Kräuter, Yasunori Watanabe, Mathieu Claireaux, Hailee R. Perrett, Tom P.L. Bijl, Marloes Grobben, Jeffrey C. Umotoy, Angela I. Schriek, Judith A. Burger, Khadija Tejjani, Nicole M. Lloyd, Thijs H. Steijaert, Marlies M. van Haaren, Kwinten Sliepen, Steven W. de Taeye, Marit J. van Gils, Max CrispinThomas Strecker, Alexander Bukreyev, Andrew B. Ward, Rogier W. Sanders

Pathology

Research output: Contribution to journal › Article › peer-review

29 Scopus citations

Abstract

The Lassa virus is endemic in parts of West Africa, and it causes hemorrhagic fever with high mortality. The development of a recombinant protein vaccine has been hampered by the instability of soluble Lassa virus glycoprotein complex (GPC) trimers, which disassemble into monomeric subunits after expression. Here, we use two-component protein nanoparticles consisting of trimeric and pentameric subunits to stabilize GPC in a trimeric conformation. These GPC nanoparticles present twenty prefusion GPC trimers on the surface of an icosahedral particle. Cryo-EM studies of GPC nanoparticles demonstrated a well-ordered structure and yielded a high-resolution structure of an unliganded GPC. These nanoparticles induced potent humoral immune responses in rabbits and protective immunity against the lethal Lassa virus challenge in guinea pigs. Additionally, we isolated a neutralizing antibody that mapped to the putative receptor-binding site, revealing a previously undefined site of vulnerability. Collectively, these findings offer potential approaches to vaccine and therapeutic design for the Lassa virus.

Original language	English (US)
Pages (from-to)	1759-1772.e12
Journal	Cell Host and Microbe
Volume	30
Issue number	12
DOIs	https://doi.org/10.1016/j.chom.2022.10.018
State	Published - Dec 14 2022

Keywords

Lassa virus
antibody
challenge study
cryo-EM
nanoparticles
vaccine

ASJC Scopus subject areas

Parasitology
Microbiology
Virology

Access to Document

10.1016/j.chom.2022.10.018

Cite this

Brouwer, P. J. M., Antanasijevic, A., Ronk, A. J., Müller-Kräuter, H., Watanabe, Y., Claireaux, M., Perrett, H. R., Bijl, T. P. L., Grobben, M., Umotoy, J. C., Schriek, A. I., Burger, J. A., Tejjani, K., Lloyd, N. M., Steijaert, T. H., van Haaren, M. M., Sliepen, K., de Taeye, S. W., van Gils, M. J., ... Sanders, R. W. (2022). Lassa virus glycoprotein nanoparticles elicit neutralizing antibody responses and protection. Cell Host and Microbe, 30(12), 1759-1772.e12. https://doi.org/10.1016/j.chom.2022.10.018

Brouwer, PJM, Antanasijevic, A, Ronk, AJ, Müller-Kräuter, H, Watanabe, Y, Claireaux, M, Perrett, HR, Bijl, TPL, Grobben, M, Umotoy, JC, Schriek, AI, Burger, JA, Tejjani, K, Lloyd, NM, Steijaert, TH, van Haaren, MM, Sliepen, K, de Taeye, SW, van Gils, MJ, Crispin, M, Strecker, T, Bukreyev, A, Ward, AB & Sanders, RW 2022, 'Lassa virus glycoprotein nanoparticles elicit neutralizing antibody responses and protection', Cell Host and Microbe, vol. 30, no. 12, pp. 1759-1772.e12. https://doi.org/10.1016/j.chom.2022.10.018

@article{4b53ef1ffdad4754b61de3af39c5d3f2,

title = "Lassa virus glycoprotein nanoparticles elicit neutralizing antibody responses and protection",

abstract = "The Lassa virus is endemic in parts of West Africa, and it causes hemorrhagic fever with high mortality. The development of a recombinant protein vaccine has been hampered by the instability of soluble Lassa virus glycoprotein complex (GPC) trimers, which disassemble into monomeric subunits after expression. Here, we use two-component protein nanoparticles consisting of trimeric and pentameric subunits to stabilize GPC in a trimeric conformation. These GPC nanoparticles present twenty prefusion GPC trimers on the surface of an icosahedral particle. Cryo-EM studies of GPC nanoparticles demonstrated a well-ordered structure and yielded a high-resolution structure of an unliganded GPC. These nanoparticles induced potent humoral immune responses in rabbits and protective immunity against the lethal Lassa virus challenge in guinea pigs. Additionally, we isolated a neutralizing antibody that mapped to the putative receptor-binding site, revealing a previously undefined site of vulnerability. Collectively, these findings offer potential approaches to vaccine and therapeutic design for the Lassa virus.",

keywords = "Lassa virus, antibody, challenge study, cryo-EM, nanoparticles, vaccine",

author = "Brouwer, {Philip J.M.} and Aleksandar Antanasijevic and Ronk, {Adam J.} and Helena M{\"u}ller-Kr{\"a}uter and Yasunori Watanabe and Mathieu Claireaux and Perrett, {Hailee R.} and Bijl, {Tom P.L.} and Marloes Grobben and Umotoy, {Jeffrey C.} and Schriek, {Angela I.} and Burger, {Judith A.} and Khadija Tejjani and Lloyd, {Nicole M.} and Steijaert, {Thijs H.} and {van Haaren}, {Marlies M.} and Kwinten Sliepen and {de Taeye}, {Steven W.} and {van Gils}, {Marit J.} and Max Crispin and Thomas Strecker and Alexander Bukreyev and Ward, {Andrew B.} and Sanders, {Rogier W.}",

note = "Publisher Copyright: {\textcopyright} 2022 The Author(s)",

year = "2022",

month = dec,

day = "14",

doi = "10.1016/j.chom.2022.10.018",

language = "English (US)",

volume = "30",

pages = "1759--1772.e12",

journal = "Cell Host and Microbe",

issn = "1931-3128",

publisher = "Cell Press",

number = "12",

}

TY - JOUR

T1 - Lassa virus glycoprotein nanoparticles elicit neutralizing antibody responses and protection

AU - Brouwer, Philip J.M.

AU - Antanasijevic, Aleksandar

AU - Ronk, Adam J.

AU - Müller-Kräuter, Helena

AU - Watanabe, Yasunori

AU - Claireaux, Mathieu

AU - Perrett, Hailee R.

AU - Bijl, Tom P.L.

AU - Grobben, Marloes

AU - Umotoy, Jeffrey C.

AU - Schriek, Angela I.

AU - Burger, Judith A.

AU - Tejjani, Khadija

AU - Lloyd, Nicole M.

AU - Steijaert, Thijs H.

AU - van Haaren, Marlies M.

AU - Sliepen, Kwinten

AU - de Taeye, Steven W.

AU - van Gils, Marit J.

AU - Crispin, Max

AU - Strecker, Thomas

AU - Bukreyev, Alexander

AU - Ward, Andrew B.

AU - Sanders, Rogier W.

PY - 2022/12/14

Y1 - 2022/12/14

N2 - The Lassa virus is endemic in parts of West Africa, and it causes hemorrhagic fever with high mortality. The development of a recombinant protein vaccine has been hampered by the instability of soluble Lassa virus glycoprotein complex (GPC) trimers, which disassemble into monomeric subunits after expression. Here, we use two-component protein nanoparticles consisting of trimeric and pentameric subunits to stabilize GPC in a trimeric conformation. These GPC nanoparticles present twenty prefusion GPC trimers on the surface of an icosahedral particle. Cryo-EM studies of GPC nanoparticles demonstrated a well-ordered structure and yielded a high-resolution structure of an unliganded GPC. These nanoparticles induced potent humoral immune responses in rabbits and protective immunity against the lethal Lassa virus challenge in guinea pigs. Additionally, we isolated a neutralizing antibody that mapped to the putative receptor-binding site, revealing a previously undefined site of vulnerability. Collectively, these findings offer potential approaches to vaccine and therapeutic design for the Lassa virus.

AB - The Lassa virus is endemic in parts of West Africa, and it causes hemorrhagic fever with high mortality. The development of a recombinant protein vaccine has been hampered by the instability of soluble Lassa virus glycoprotein complex (GPC) trimers, which disassemble into monomeric subunits after expression. Here, we use two-component protein nanoparticles consisting of trimeric and pentameric subunits to stabilize GPC in a trimeric conformation. These GPC nanoparticles present twenty prefusion GPC trimers on the surface of an icosahedral particle. Cryo-EM studies of GPC nanoparticles demonstrated a well-ordered structure and yielded a high-resolution structure of an unliganded GPC. These nanoparticles induced potent humoral immune responses in rabbits and protective immunity against the lethal Lassa virus challenge in guinea pigs. Additionally, we isolated a neutralizing antibody that mapped to the putative receptor-binding site, revealing a previously undefined site of vulnerability. Collectively, these findings offer potential approaches to vaccine and therapeutic design for the Lassa virus.

KW - Lassa virus

KW - antibody

KW - challenge study

KW - cryo-EM

KW - nanoparticles

KW - vaccine

UR - http://www.scopus.com/inward/record.url?scp=85143512375&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85143512375&partnerID=8YFLogxK

U2 - 10.1016/j.chom.2022.10.018

DO - 10.1016/j.chom.2022.10.018

M3 - Article

C2 - 36400021

AN - SCOPUS:85143512375

SN - 1931-3128

VL - 30

SP - 1759-1772.e12

JO - Cell Host and Microbe

JF - Cell Host and Microbe

IS - 12

ER -

Lassa virus glycoprotein nanoparticles elicit neutralizing antibody responses and protection

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this