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

<div class='caption-title'>Dissociation of GI.1 norovirus VLPs leads to exposure of occluded epitopes.</div>
<div class='caption-title'>Structure-based design of interprotomer disulfides between VP1 monomers leads to stabilized particles with increased thermal stability of the shell domain.</div>
<div class='caption-title'>Cryo-EM reconstruction of GI.1 DS1 VLP provides details of interprotomer disulfide bonds between Cys116 and Cys193.</div>
Verardi R, Lindesmith LC, Tsybovsky Y, Gorman J, Chuang GY, Edwards CE, Brewer-Jensen PD, Mallory ML, Ou L, Schön A, Shi W, Tully ES, Georgiou G, Baric RS, Kwong PD
OpenAccess logo NPJ Vaccines 5 110 (2020)
Cited: 5 times
EuropePMC logo PMID: 33318483

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.

Articles - 7kjp mentioned but not cited (1)

  1. Disulfide stabilization of human norovirus GI.1 virus-like particles focuses immune response toward blockade epitopes. Verardi R, Lindesmith LC, Tsybovsky Y, Gorman J, Chuang GY, Edwards CE, Brewer-Jensen PD, Mallory ML, Ou L, Schön A, Shi W, Tully ES, Georgiou G, Baric RS, Kwong PD. NPJ Vaccines 5 110 (2020)


Reviews citing this publication (1)

  1. Self-Assembling Protein Nanoparticles in the Design of Vaccines: 2022 Update. Morales-Hernández S, Ugidos-Damboriena N, López-Sagaseta J. Vaccines (Basel) 10 1447 (2022)

Articles citing this publication (3)

  1. Altering the Immunogenicity of Hemagglutinin Immunogens by Hyperglycosylation and Disulfide Stabilization. Thornlow DN, Macintyre AN, Oguin TH, Karlsson AB, Stover EL, Lynch HE, Sempowski GD, Schmidt AG. Front Immunol 12 737973 (2021)
  2. Chimeric VLPs Bearing VP60 from Two Serotypes of Rabbit Haemorrhagic Disease Virus Are Protective against Both Viruses. Dalton KP, Alvarado C, Reytor E, Del Carmen Nuñez M, Podadera A, Martínez-Alonso D, Alonso JMM, Nicieza I, Gómez-Sebastián S, Dalton RM, Parra F, Escribano JM. Vaccines (Basel) 9 1005 (2021)
  3. A non-human primate model for human norovirus infection. Rimkute I, Chaimongkol N, Woods KD, Nagata BM, Darko S, Gudbole S, Henry AR, Sosnovtsev SV, Olia AS, Verardi R, Bok K, Todd JP, Woodward R, Kwong PD, Douek DC, Alves DA, Green KY, Roederer M. Nat Microbiol 9 776-786 (2024)


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