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:https://doi.org/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

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

15 Citations (Scopus)

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
Pages (from-to)	1759-1772.e12
Journal	CELL Host & Microbe
Volume	30
Issue number	12
Early online date	17 Nov 2022
DOIs	https://doi.org/10.1016/j.chom.2022.10.018
Publication status	Published - 14 Dec 2022

Keywords

Lassa virus
antibody
challenge study
cryo-EM
nanoparticles
vaccine

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https://doi.org/10.1016/j.chom.2022.10.018

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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 & Microbe, 30(12), 1759-1772.e12. https://doi.org/10.1016/j.chom.2022.10.018

@article{aaad4c1e3d964db0973552aea2896cfc,

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 = "Funding Information: We thank Robin Shattock and Paul McKay at Imperial College London for kindly sharing the full-length lineage IV (Josiah) GPC vector, Dietmar Katingen and Philipp Mundsperger at Polymun Scientific for providing the SE adjuvant, Rashmi Ravichandran and Neil King at the Institute for Protein Design for sharing purified I53-50B, and Thijn Brummelkamp for sharing an Fc-tagged LAMP-1 expression plasmid. We thank Gotthard Ludwig and Sebastian Schmidt from the biosafety level 4 facility at the Philipps-University of Marburg for technical assistance. The authors also thank Bill Anderson and Hannah Turner from The Scripps Research Institute for their help with electron microscopy experiments. The rabbit and guinea pig image in Figure 4 was created with BioRender.com . This work was supported by a Rubicon fellowship from the Netherlands Organisation for Scientific Research (#452020226 NWO; to P.J.M.B.), the Vici fellowship from the Netherlands Organisation for Scientific Research (NWO; to R.W.S.), the Fondation Dormeur, Vaduz (to R.W.S. and to M.J.v.G.), and the Bill and Melinda Gates Foundation through grant OPP1170236 (to A.B.W.). A.A. was supported by the amfAR Mathilde Krim Fellowship in Biomedical Research (#110182-69-RKVA). T.S. received funding from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)—projektnummer 197785619/SFB1021. M. Crispin is supported by the International AIDS Vaccine Initiative (IAVI) through the Collaboration for AIDS Vaccine Discovery (CAVD) grant, INV-008352/OPP1153692 funded by the Bill and Melinda Gates Foundation. Funding Information: We thank Robin Shattock and Paul McKay at Imperial College London for kindly sharing the full-length lineage IV (Josiah) GPC vector, Dietmar Katingen and Philipp Mundsperger at Polymun Scientific for providing the SE adjuvant, Rashmi Ravichandran and Neil King at the Institute for Protein Design for sharing purified I53-50B, and Thijn Brummelkamp for sharing an Fc-tagged LAMP-1 expression plasmid. We thank Gotthard Ludwig and Sebastian Schmidt from the biosafety level 4 facility at the Philipps-University of Marburg for technical assistance. The authors also thank Bill Anderson and Hannah Turner from The Scripps Research Institute for their help with electron microscopy experiments. The rabbit and guinea pig image in Figure 4 was created with BioRender.com. This work was supported by a Rubicon fellowship from the Netherlands Organisation for Scientific Research (#452020226 NWO; to P.J.M.B.), the Vici fellowship from the Netherlands Organisation for Scientific Research (NWO; to R.W.S.), the Fondation Dormeur, Vaduz (to R.W.S. and to M.J.v.G.), and the Bill and Melinda Gates Foundation through grant OPP1170236 (to A.B.W.). A.A. was supported by the amfAR Mathilde Krim Fellowship in Biomedical Research (#110182-69-RKVA). T.S. received funding from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)—projektnummer 197785619/SFB1021. M. Crispin is supported by the International AIDS Vaccine Initiative (IAVI) through the Collaboration for AIDS Vaccine Discovery (CAVD) grant, INV-008352/OPP1153692 funded by the Bill and Melinda Gates Foundation. P.J.M.B. A.A. A.J.R. H.M.-K. T.S. A.B. A.B.W. and R.W.S. conceived and designed experiments. P.J.M.B. A.A. A.J.R. H.M.-K. Y.W. M. Claireaux, H.R.P. T.P.L.B. M.G. J.C.U. A.I.S. J.A.B. K.T. N.M.L. and T.H.S. performed the experiments. P.J.M.B. A.A. A.J.R. H.M.-K. Y.W. M. Claireaux, M.M.v.H. S.W.d.T. and M.J.v.G. set up experimental assays. P.J.M.B. A.A. A.J.R. H.M.-K, Y.W. M. Claireaux, M. Crispin, A.B.W. and R.W.S. analyzed and interpreted data. K.S. shared the HCV E1E2-I53-50A reagent for FACS sorting. P.J.M.B. A.A. A.J.R. H.M.-K. Y.W. M.G. J.C.U. A.I.S. T.S. A.B.W. and R.W.S. wrote the manuscript with input from all authors. Y.W. has taken up a position at AstraZeneca; all experimental work was performed prior to this development. We support inclusive, diverse, and equitable conduct of research. Publisher Copyright: {\textcopyright} 2022 The Author(s)",

year = "2022",

month = dec,

day = "14",

doi = "https://doi.org/10.1016/j.chom.2022.10.018",

language = "English",

volume = "30",

pages = "1759--1772.e12",

journal = "CELL Host & Microbe",

issn = "1931-3128",

publisher = "Cell Press",

number = "12",

}

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 & Microbe, vol. 30, no. 12, pp. 1759-1772.e12. https://doi.org/10.1016/j.chom.2022.10.018

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.

N1 - Funding Information: We thank Robin Shattock and Paul McKay at Imperial College London for kindly sharing the full-length lineage IV (Josiah) GPC vector, Dietmar Katingen and Philipp Mundsperger at Polymun Scientific for providing the SE adjuvant, Rashmi Ravichandran and Neil King at the Institute for Protein Design for sharing purified I53-50B, and Thijn Brummelkamp for sharing an Fc-tagged LAMP-1 expression plasmid. We thank Gotthard Ludwig and Sebastian Schmidt from the biosafety level 4 facility at the Philipps-University of Marburg for technical assistance. The authors also thank Bill Anderson and Hannah Turner from The Scripps Research Institute for their help with electron microscopy experiments. The rabbit and guinea pig image in Figure 4 was created with BioRender.com . This work was supported by a Rubicon fellowship from the Netherlands Organisation for Scientific Research (#452020226 NWO; to P.J.M.B.), the Vici fellowship from the Netherlands Organisation for Scientific Research (NWO; to R.W.S.), the Fondation Dormeur, Vaduz (to R.W.S. and to M.J.v.G.), and the Bill and Melinda Gates Foundation through grant OPP1170236 (to A.B.W.). A.A. was supported by the amfAR Mathilde Krim Fellowship in Biomedical Research (#110182-69-RKVA). T.S. received funding from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)—projektnummer 197785619/SFB1021. M. Crispin is supported by the International AIDS Vaccine Initiative (IAVI) through the Collaboration for AIDS Vaccine Discovery (CAVD) grant, INV-008352/OPP1153692 funded by the Bill and Melinda Gates Foundation. Funding Information: We thank Robin Shattock and Paul McKay at Imperial College London for kindly sharing the full-length lineage IV (Josiah) GPC vector, Dietmar Katingen and Philipp Mundsperger at Polymun Scientific for providing the SE adjuvant, Rashmi Ravichandran and Neil King at the Institute for Protein Design for sharing purified I53-50B, and Thijn Brummelkamp for sharing an Fc-tagged LAMP-1 expression plasmid. We thank Gotthard Ludwig and Sebastian Schmidt from the biosafety level 4 facility at the Philipps-University of Marburg for technical assistance. The authors also thank Bill Anderson and Hannah Turner from The Scripps Research Institute for their help with electron microscopy experiments. The rabbit and guinea pig image in Figure 4 was created with BioRender.com. This work was supported by a Rubicon fellowship from the Netherlands Organisation for Scientific Research (#452020226 NWO; to P.J.M.B.), the Vici fellowship from the Netherlands Organisation for Scientific Research (NWO; to R.W.S.), the Fondation Dormeur, Vaduz (to R.W.S. and to M.J.v.G.), and the Bill and Melinda Gates Foundation through grant OPP1170236 (to A.B.W.). A.A. was supported by the amfAR Mathilde Krim Fellowship in Biomedical Research (#110182-69-RKVA). T.S. received funding from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)—projektnummer 197785619/SFB1021. M. Crispin is supported by the International AIDS Vaccine Initiative (IAVI) through the Collaboration for AIDS Vaccine Discovery (CAVD) grant, INV-008352/OPP1153692 funded by the Bill and Melinda Gates Foundation. P.J.M.B. A.A. A.J.R. H.M.-K. T.S. A.B. A.B.W. and R.W.S. conceived and designed experiments. P.J.M.B. A.A. A.J.R. H.M.-K. Y.W. M. Claireaux, H.R.P. T.P.L.B. M.G. J.C.U. A.I.S. J.A.B. K.T. N.M.L. and T.H.S. performed the experiments. P.J.M.B. A.A. A.J.R. H.M.-K. Y.W. M. Claireaux, M.M.v.H. S.W.d.T. and M.J.v.G. set up experimental assays. P.J.M.B. A.A. A.J.R. H.M.-K, Y.W. M. Claireaux, M. Crispin, A.B.W. and R.W.S. analyzed and interpreted data. K.S. shared the HCV E1E2-I53-50A reagent for FACS sorting. P.J.M.B. A.A. A.J.R. H.M.-K. Y.W. M.G. J.C.U. A.I.S. T.S. A.B.W. and R.W.S. wrote the manuscript with input from all authors. Y.W. has taken up a position at AstraZeneca; all experimental work was performed prior to this development. We support inclusive, diverse, and equitable conduct of research. Publisher Copyright: © 2022 The Author(s)

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

U2 - https://doi.org/10.1016/j.chom.2022.10.018

DO - https://doi.org/10.1016/j.chom.2022.10.018

M3 - Article

C2 - 36400021

SN - 1931-3128

VL - 30

SP - 1759-1772.e12

JO - CELL Host & Microbe

JF - CELL Host & Microbe

IS - 12

ER -

Lassa virus glycoprotein nanoparticles elicit neutralizing antibody responses and protection

Abstract

Keywords

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