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Lassa virus glycoprotein nanoparticles elicit neutralizing antibody responses and protection

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

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.

Animals, Antibodies, Neutralizing, Glycoproteins, Guinea Pigs, Lassa Fever/prevention & control, Lassa virus/chemistry, Nanoparticles, Rabbits, Vaccines, Synthetic
1931-3128
1759-1772.e12
Brouwer, Philip J M
9a3ab106-b09e-4f03-a4ff-bb9dcf99eeed
Antanasijevic, Aleksandar
f87b3a62-684c-41e3-8898-5ec80d6d50c3
Ronk, Adam J
96975035-8a45-4523-ab41-e0747894a875
Müller-Kräuter, Helena
452ceb6a-4497-4f65-9a39-5c1a7cdc1ede
Watanabe, Yasunori
8c0ee4af-a293-4de5-9036-3ce2051b380c
Claireaux, Mathieu
1fe67610-b7f0-4a30-9307-12bc53b37f52
Perrett, Hailee R
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Bijl, Tom P L
7c64fdad-a591-419c-9d15-394a6561fd7e
Grobben, Marloes
eb0bdab2-d093-49f8-98f6-d906724261f1
Umotoy, Jeffrey C
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Schriek, Angela I
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Burger, Judith A
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Tejjani, Khadija
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Lloyd, Nicole M
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Steijaert, Thijs H
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van Haaren, Marlies M
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Sliepen, Kwinten
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de Taeye, Steven W
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van Gils, Marit J
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Crispin, Max
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Strecker, Thomas
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Bukreyev, Alexander
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Ward, Andrew B
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Sanders, Rogier W
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Brouwer, Philip J M
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Antanasijevic, Aleksandar
f87b3a62-684c-41e3-8898-5ec80d6d50c3
Ronk, Adam J
96975035-8a45-4523-ab41-e0747894a875
Müller-Kräuter, Helena
452ceb6a-4497-4f65-9a39-5c1a7cdc1ede
Watanabe, Yasunori
8c0ee4af-a293-4de5-9036-3ce2051b380c
Claireaux, Mathieu
1fe67610-b7f0-4a30-9307-12bc53b37f52
Perrett, Hailee R
1b2ab392-db4b-4dc1-b957-874fd64458c4
Bijl, Tom P L
7c64fdad-a591-419c-9d15-394a6561fd7e
Grobben, Marloes
eb0bdab2-d093-49f8-98f6-d906724261f1
Umotoy, Jeffrey C
223eb75c-f161-44fc-942f-1b6884f8bf06
Schriek, Angela I
32430ab2-af9c-4051-8d36-43517a0c8819
Burger, Judith A
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Tejjani, Khadija
283963de-0ffe-4a05-9623-95d1fb899695
Lloyd, Nicole M
6248cb6f-e611-42b0-b6a7-eedc6f9eec23
Steijaert, Thijs H
62d8d8c0-d2bc-42a1-839c-ef137f7e9015
van Haaren, Marlies M
45cb02f2-360d-4e13-bbba-f9f97ecb229b
Sliepen, Kwinten
d2551fe9-7d04-459e-85b5-29fc4b35317a
de Taeye, Steven W
3ee19998-9ef7-4630-8a9b-da852b834225
van Gils, Marit J
f2e1e7f1-36a1-4270-8509-d17a10ddb9a6
Crispin, Max
cd980957-0943-4b89-b2b2-710f01f33bc9
Strecker, Thomas
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Bukreyev, Alexander
d1d94e12-58d2-4508-8d19-eeb3ccf9f1f9
Ward, Andrew B
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Sanders, Rogier W
d3b67c2c-c725-42e7-b972-50b30be67c74

Brouwer, Philip J M, Antanasijevic, Aleksandar, Ronk, Adam J, Müller-Kräuter, Helena, Watanabe, Yasunori, Claireaux, Mathieu, Perrett, Hailee R, Bijl, Tom P L, Grobben, Marloes, Umotoy, Jeffrey C, Schriek, Angela I, Burger, Judith A, Tejjani, Khadija, Lloyd, Nicole M, Steijaert, Thijs H, van Haaren, Marlies M, Sliepen, Kwinten, de Taeye, Steven W, van Gils, Marit J, Crispin, Max, Strecker, Thomas, Bukreyev, Alexander, Ward, Andrew B and Sanders, Rogier W (2022) Lassa virus glycoprotein nanoparticles elicit neutralizing antibody responses and protection. Cell Host & Microbe, 30 (12), 1759-1772.e12. (doi:10.1016/j.chom.2022.10.018).

Record type: Article

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.

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Accepted/In Press date: 25 October 2022
e-pub ahead of print date: 17 November 2022
Published date: 14 December 2022
Additional Information: Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.
Keywords: Animals, Antibodies, Neutralizing, Glycoproteins, Guinea Pigs, Lassa Fever/prevention & control, Lassa virus/chemistry, Nanoparticles, Rabbits, Vaccines, Synthetic
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Identifiers

Local EPrints ID: 473593
URI: http://eprints.soton.ac.uk/id/eprint/473593
DOI: doi:10.1016/j.chom.2022.10.018
ISSN: 1931-3128
PURE UUID: 6d1eda2f-707a-41c4-bd95-1eff362c6dc3
ORCID for Max Crispin: ORCID iD orcid.org/0000-0002-1072-2694

Catalogue record

Date deposited: 24 Jan 2023 17:41
Last modified: 08 May 2024 01:51

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Contributors

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

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