Disulfide stabilization of human norovirus GI.1 virus-like particles focuses immune response toward blockade epitopes

Abstract Human noroviruses are non-enveloped, single-strand RNA viruses that cause pandemic outbreaks of acute gastroenteritis. A bivalent vaccine containing GI.1 and GII.4 virus-like particles (VLPs) has been shown to be safe and highly immunogenic, but its efficacy and durability have been limited...

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Autores principales:	Raffaello Verardi, Lisa C. Lindesmith, Yaroslav Tsybovsky, Jason Gorman, Gwo-Yu Chuang, Caitlin E. Edwards, Paul D. Brewer-Jensen, Michael L. Mallory, Li Ou, Arne Schön, Wei Shi, Ena S. Tully, George Georgiou, Ralph S. Baric, Peter D. Kwong
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Immunologic diseases. Allergy RC581-607 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/291f486fe191490c902890335db78af5
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spelling	oai:doaj.org-article:291f486fe191490c902890335db78af52021-12-02T12:42:26ZDisulfide stabilization of human norovirus GI.1 virus-like particles focuses immune response toward blockade epitopes10.1038/s41541-020-00260-w2059-0105https://doaj.org/article/291f486fe191490c902890335db78af52020-12-01T00:00:00Zhttps://doi.org/10.1038/s41541-020-00260-whttps://doaj.org/toc/2059-0105Abstract Human noroviruses are non-enveloped, single-strand RNA viruses that cause pandemic outbreaks of acute gastroenteritis. A bivalent vaccine containing GI.1 and GII.4 virus-like particles (VLPs) has been shown to be safe and highly immunogenic, but its efficacy and durability have been limited. Here, we show that norovirus GI.1 VLPs are unstable and contain a substantial fraction of dissociated VLP components. Broadly reactive, non-neutralizing antibodies isolated from vaccinated donors bound to the dissociated components, but not to the intact VLPs. Engineering of interprotomer disulfide bonds within the shell domain prevented disassembly of the VLPs, while preserving antibody accessibility to blockade epitopes. Without adjuvant, mice immunized with stabilized GI.1 VLPs developed faster blockade antibody titers compared to immunization with wild-type GI.1 VLPs. In addition, immunization with stabilized particles focused immune responses toward surface-exposed epitopes and away from occluded epitopes. Overall, disulfide-stabilized norovirus GI.1 VLPs elicited improved responses over the non-disulfide-stabilized version, suggesting their promise as candidate vaccines.Raffaello VerardiLisa C. LindesmithYaroslav TsybovskyJason GormanGwo-Yu ChuangCaitlin E. EdwardsPaul D. Brewer-JensenMichael L. MalloryLi OuArne SchönWei ShiEna S. TullyGeorge GeorgiouRalph S. BaricPeter D. KwongNature PortfolioarticleImmunologic diseases. AllergyRC581-607Neoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENnpj Vaccines, Vol 5, Iss 1, Pp 1-10 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Immunologic diseases. Allergy RC581-607 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Raffaello Verardi Lisa C. Lindesmith Yaroslav Tsybovsky Jason Gorman Gwo-Yu Chuang Caitlin E. Edwards Paul D. Brewer-Jensen Michael L. Mallory Li Ou Arne Schön Wei Shi Ena S. Tully George Georgiou Ralph S. Baric Peter D. Kwong Disulfide stabilization of human norovirus GI.1 virus-like particles focuses immune response toward blockade epitopes
description	Abstract Human noroviruses are non-enveloped, single-strand RNA viruses that cause pandemic outbreaks of acute gastroenteritis. A bivalent vaccine containing GI.1 and GII.4 virus-like particles (VLPs) has been shown to be safe and highly immunogenic, but its efficacy and durability have been limited. Here, we show that norovirus GI.1 VLPs are unstable and contain a substantial fraction of dissociated VLP components. Broadly reactive, non-neutralizing antibodies isolated from vaccinated donors bound to the dissociated components, but not to the intact VLPs. Engineering of interprotomer disulfide bonds within the shell domain prevented disassembly of the VLPs, while preserving antibody accessibility to blockade epitopes. Without adjuvant, mice immunized with stabilized GI.1 VLPs developed faster blockade antibody titers compared to immunization with wild-type GI.1 VLPs. In addition, immunization with stabilized particles focused immune responses toward surface-exposed epitopes and away from occluded epitopes. Overall, disulfide-stabilized norovirus GI.1 VLPs elicited improved responses over the non-disulfide-stabilized version, suggesting their promise as candidate vaccines.
format	article
author	Raffaello Verardi Lisa C. Lindesmith Yaroslav Tsybovsky Jason Gorman Gwo-Yu Chuang Caitlin E. Edwards Paul D. Brewer-Jensen Michael L. Mallory Li Ou Arne Schön Wei Shi Ena S. Tully George Georgiou Ralph S. Baric Peter D. Kwong
author_facet	Raffaello Verardi Lisa C. Lindesmith Yaroslav Tsybovsky Jason Gorman Gwo-Yu Chuang Caitlin E. Edwards Paul D. Brewer-Jensen Michael L. Mallory Li Ou Arne Schön Wei Shi Ena S. Tully George Georgiou Ralph S. Baric Peter D. Kwong
author_sort	Raffaello Verardi
title	Disulfide stabilization of human norovirus GI.1 virus-like particles focuses immune response toward blockade epitopes
title_short	Disulfide stabilization of human norovirus GI.1 virus-like particles focuses immune response toward blockade epitopes
title_full	Disulfide stabilization of human norovirus GI.1 virus-like particles focuses immune response toward blockade epitopes
title_fullStr	Disulfide stabilization of human norovirus GI.1 virus-like particles focuses immune response toward blockade epitopes
title_full_unstemmed	Disulfide stabilization of human norovirus GI.1 virus-like particles focuses immune response toward blockade epitopes
title_sort	disulfide stabilization of human norovirus gi.1 virus-like particles focuses immune response toward blockade epitopes
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/291f486fe191490c902890335db78af5
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Disulfide stabilization of human norovirus GI.1 virus-like particles focuses immune response toward blockade epitopes

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