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

Affiliation
Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA 24060, USA;(C.H.);(P.Z.);(S.S.);(C.N.);(V.P.);(A.F.);(M.F.);(K.K.);(S.O.);(Y.L.)
Hensley, Casey;
Affiliation
CureVac SE, 72076 Tübingen, Germany;(S.R.);(B.P.);(S.R.)
Roier, Sandro;
Affiliation
Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA 24060, USA;(C.H.);(P.Z.);(S.S.);(C.N.);(V.P.);(A.F.);(M.F.);(K.K.);(S.O.);(Y.L.)
Zhou, Peng;
Affiliation
Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA 24060, USA;(C.H.);(P.Z.);(S.S.);(C.N.);(V.P.);(A.F.);(M.F.);(K.K.);(S.O.);(Y.L.)
Schnur, Sofia;
Affiliation
Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA 24060, USA;(C.H.);(P.Z.);(S.S.);(C.N.);(V.P.);(A.F.);(M.F.);(K.K.);(S.O.);(Y.L.)
Nyblade, Charlotte;
Affiliation
Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA 24060, USA;(C.H.);(P.Z.);(S.S.);(C.N.);(V.P.);(A.F.);(M.F.);(K.K.);(S.O.);(Y.L.)
Parreno, Viviana;
Affiliation
Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA 24060, USA;(C.H.);(P.Z.);(S.S.);(C.N.);(V.P.);(A.F.);(M.F.);(K.K.);(S.O.);(Y.L.)
Frazier, Annie;
Affiliation
Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA 24060, USA;(C.H.);(P.Z.);(S.S.);(C.N.);(V.P.);(A.F.);(M.F.);(K.K.);(S.O.);(Y.L.)
Frazier, Maggie;
Affiliation
Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA 24060, USA;(C.H.);(P.Z.);(S.S.);(C.N.);(V.P.);(A.F.);(M.F.);(K.K.);(S.O.);(Y.L.)
Kiley, Kelsey;
Affiliation
Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA 24060, USA;(C.H.);(P.Z.);(S.S.);(C.N.);(V.P.);(A.F.);(M.F.);(K.K.);(S.O.);(Y.L.)
O’Brien, Samantha;
Affiliation
Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA 24060, USA;(C.H.);(P.Z.);(S.S.);(C.N.);(V.P.);(A.F.);(M.F.);(K.K.);(S.O.);(Y.L.)
Liang, Yu;
Affiliation
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA;(B.T.M.);(R.W.);(C.M.)
Mayer, Bryan T.;
Affiliation
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA;(B.T.M.);(R.W.);(C.M.)
Wu, Ruizhe;
Affiliation
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA;(B.T.M.);(R.W.);(C.M.)
Mahoney, Celia;
Affiliation
Department of Pediatrics, University of Cincinnati College of Medicine, and Division of Infectious Diseases, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA;
McNeal, Monica M.;
ORCID
0000-0001-7431-0683
Affiliation
CureVac SE, 72076 Tübingen, Germany;(S.R.);(B.P.);(S.R.)
Petsch, Benjamin;
Affiliation
CureVac SE, 72076 Tübingen, Germany;(S.R.);(B.P.);(S.R.)
Rauch, Susanne;
ORCID
0000-0003-0709-5228
Affiliation
Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA 24060, USA;(C.H.);(P.Z.);(S.S.);(C.N.);(V.P.);(A.F.);(M.F.);(K.K.);(S.O.);(Y.L.)
Yuan, Lijuan

Human 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.

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Editor:
Meurens, François
Published in:
Vaccines  
Vol. 12, No. 3 (01.03.2024)
Volume:
12
No.:
3
Date Issued:
01.03.2024
DOI:
10.3390/vaccines12030260
Language:
English
Type of Resource:
Text
Keywords:
  1. rotavirus
    Typ
    Schlagwort
  1. mRNA vaccine
    Typ
    Schlagwort
  1. gnotobiotic pigs
    Typ
    Schlagwort
  1. P2-VP8*
    Typ
    Schlagwort
  1. diarrhea
    Typ
    Schlagwort
DDC:
610 Medizin und Gesundheit

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