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mRNA-Based Vaccines Are Highly Immunogenic and Confer Protection in the Gnotobiotic Pig Model of Human Rotavirus Diarrhea

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dc.contributor.authorHensley, Caseyen
dc.contributor.authorRoier, Sandroen
dc.contributor.authorZhou, Pengen
dc.contributor.authorNyblade, Charlotteen
dc.contributor.authorParreno, Vivianaen
dc.contributor.authorFrazier, Annieen
dc.contributor.authorFrazier, Maggieen
dc.contributor.authorO'Brien, Samanthaen
dc.contributor.authorLiang, Yuen
dc.contributor.authorMayer, Bryanen
dc.contributor.authorWu, Ruizheen
dc.contributor.authorMahoney, Celiaen
dc.contributor.authorMcNeal, Monicaen
dc.contributor.authorPetsch, Benjaminen
dc.contributor.authorRauch, Susanneen
dc.contributor.authorYuan, Lijuanen
dc.date.accessioned2024-03-06T18:47:39Zen
dc.date.available2024-03-06T18:47:39Zen
dc.date.issued2024-03-01en
dc.description.abstractHuman rotavirus (HRV) is still a leading cause of severe dehydrating gastroenteritis globally, particularly in infants and children. Previously, we demonstrated the immunogenicity of mRNA-based HRV vaccine candidates expressing the viral spike protein VP8* in rodent models. In the present study, we assessed the immunogenicity and protective efficacy of two mRNA-based HRV trivalent vaccine candidates, encoding VP8* of the genotypes P[8], P[6], or P[4], in the gnotobiotic (Gn) pig model of Wa (G1P[8]) HRV infection and diarrhea. Vaccines either encoded VP8* alone fused to the universal T-cell epitope P2 (P2-VP8*) or expressed P2-VP8* as a fusion protein with lumazine synthase (LS-P2-VP8*) to allow the formation and secretion of protein particles that present VP8* on their surface. Gn pigs were randomly assigned into groups and immunized three times with either P2-VP8* (30 µg) or LS-P2-VP8* (30 µg or 12 µg). A trivalent alum-adjuvanted P2-VP8* protein vaccine or an LNP-formulated irrelevant mRNA vaccine served as the positive and negative control, respectively. Upon challenge with virulent Wa HRV, a significantly shortened duration and decreased severity of diarrhea and significant protection from virus shedding was induced by both mRNA vaccine candidates compared to the negative control. Both LS-P2-VP8* doses induced significantly higher VP8*-specific IgG antibody titers in the serum after immunizations than the negative as well as the protein control. The P[8] VP8*-specific IgG antibody-secreting cells in the ileum, spleen, and blood seven days post-challenge, as well as VP8*-specific IFN-γ-producing T-cell numbers increased in all three mRNA-vaccinated pig groups compared to the negative control. Overall, there was a clear tendency towards improved responses in LS-P2-VP8* compared to the P2-VP8*mRNA vaccine. The demonstrated strong humoral immune responses, priming for effector T cells, and the significant reduction of viral shedding and duration of diarrhea in Gn pigs provide a promising proof of concept and may provide guidance for the further development of mRNA-based rotavirus vaccines.en
dc.description.versionPublished versionen
dc.format.extentPages 1-22en
dc.format.extent22 page(s)en
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.3390/vaccines12030260en
dc.identifier.eissn2076-393Xen
dc.identifier.issue3 (260)en
dc.identifier.orcidYuan, Lijuan [0000-0003-0709-5228]en
dc.identifier.urihttps://hdl.handle.net/10919/118287en
dc.identifier.volume12en
dc.language.isoenen
dc.publisherMDPIen
dc.relation.urihttps://www.mdpi.com/journal/vaccinesen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectrotavirusen
dc.subjectmRNA vaccineen
dc.subjectgnotobiotic pigsen
dc.subjectP2-VP8*en
dc.subjectdiarrheaen
dc.titlemRNA-Based Vaccines Are Highly Immunogenic and Confer Protection in the Gnotobiotic Pig Model of Human Rotavirus Diarrheaen
dc.title.serialVaccinesen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
dc.type.otherArticleen
dcterms.dateAccepted2024-02-22en
pubs.organisational-group/Virginia Techen
pubs.organisational-group/Virginia Tech/Veterinary Medicineen
pubs.organisational-group/Virginia Tech/Veterinary Medicine/Biomedical Sciences and Pathobiologyen
pubs.organisational-group/Virginia Tech/Faculty of Health Sciencesen
pubs.organisational-group/Virginia Tech/All T&R Facultyen
pubs.organisational-group/Virginia Tech/Veterinary Medicine/CVM T&R Facultyen

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