Hensley, C.; Roier, S.; Zhou, P.; Schnur, S.; Nyblade, C.; Parreno, V.; Frazier, A.; Frazier, M.; Kiley, K.; O’Brien, S.; Liang, Y.; Mayer, B.T.; Wu, R.; Mahoney, C.; McNeal, M.M.; Petsch, B.; Rauch, S.; Yuan, L. mRNA-Based Vaccines Are Highly Immunogenic and Confer Protection in the Gnotobiotic Pig Model of Human Rotavirus Diarrhea. Vaccines2024, 12, 260.
Hensley, C.; Roier, S.; Zhou, P.; Schnur, S.; Nyblade, C.; Parreno, V.; Frazier, A.; Frazier, M.; Kiley, K.; O’Brien, S.; Liang, Y.; Mayer, B.T.; Wu, R.; Mahoney, C.; McNeal, M.M.; Petsch, B.; Rauch, S.; Yuan, L. mRNA-Based Vaccines Are Highly Immunogenic and Confer Protection in the Gnotobiotic Pig Model of Human Rotavirus Diarrhea. Vaccines 2024, 12, 260.
Hensley, C.; Roier, S.; Zhou, P.; Schnur, S.; Nyblade, C.; Parreno, V.; Frazier, A.; Frazier, M.; Kiley, K.; O’Brien, S.; Liang, Y.; Mayer, B.T.; Wu, R.; Mahoney, C.; McNeal, M.M.; Petsch, B.; Rauch, S.; Yuan, L. mRNA-Based Vaccines Are Highly Immunogenic and Confer Protection in the Gnotobiotic Pig Model of Human Rotavirus Diarrhea. Vaccines2024, 12, 260.
Hensley, C.; Roier, S.; Zhou, P.; Schnur, S.; Nyblade, C.; Parreno, V.; Frazier, A.; Frazier, M.; Kiley, K.; O’Brien, S.; Liang, Y.; Mayer, B.T.; Wu, R.; Mahoney, C.; McNeal, M.M.; Petsch, B.; Rauch, S.; Yuan, L. mRNA-Based Vaccines Are Highly Immunogenic and Confer Protection in the Gnotobiotic Pig Model of Human Rotavirus Diarrhea. Vaccines 2024, 12, 260.
Abstract
Human rotavirus (HRV) is still a leading cause of severe dehydrating gastroenteritis globally, particularly in infants and children. Previously, we demonstrated 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 positive and negative control, respectively. Upon challenge with virulent Wa HRV, 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 anti-body-secreting cells in ileum, spleen and blood seven days post-challenge as well as VP8*-specific IFN--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 P2-VP8*mRNA vaccine. The demonstrated strong humoral immune responses, priming for effector T cells, and significant reduction of viral shedding and duration of diarrhea in Gn pigs provide a promising proof of concept and may provide guidance for further development of mRNA-based rotavirus vaccines.
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