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Simplified Reverse Genetics Method to Recover Recombinant Rotaviruses Expressing Reporter Proteins
Published on: April 17, 2020
mRNA-based VP8* nanoparticle vaccines against rotavirus are highly immunogenic in rodents
Sandro Roier1, Vidya Mangala Prasad2,3, Monica M McNeal4
1CureVac SE, Tübingen, Germany.
Abstract:
Despite the availability of live-attenuated oral vaccines, rotavirus remains a major cause of severe childhood diarrhea worldwide. Due to the growing demand for parenteral rotavirus vaccines, we developed mRNA-based vaccine candidates targeting the viral spike protein VP8*. Our monomeric P2 (universal T cell epitope)-VP8* mRNA design is equivalent to a protein vaccine currently in clinical development, while LS (lumazine synthase)-P2-VP8* was designed to form nanoparticles. Cyro-electron microscopy and western blotting-based data presented here suggest that proteins derived from LS-P2-VP8* mRNA are secreted in vitro and self-assemble into 60-mer nanoparticles displaying VP8*. mRNA encoded VP8* was immunogenic in rodents and introduced both humoral and cellular responses. LS-P2-VP8* induced superior humoral responses to P2-VP8* in guinea pigs, both as monovalent and trivalent vaccines, with encouraging responses detected against the most prevalent P genotypes. Overall, our data provide evidence that trivalent LS-P2-VP8* represents a promising mRNA-based next-generation rotavirus vaccine candidate.
Insights
New mRNA rotavirus vaccine candidates show promise. The nanoparticle-forming LS-P2-VP8* mRNA vaccine induced superior immune responses in animal models compared to a standard P2-VP8* mRNA vaccine.
Area of Science:
- Vaccinology
- Molecular Biology
- Virology
Background:
- Rotavirus is a leading cause of severe childhood diarrhea globally, necessitating improved vaccine strategies.
- Existing oral rotavirus vaccines have limitations, driving demand for alternative parenteral vaccine approaches.
- Messenger RNA (mRNA) technology offers a platform for developing novel vaccine candidates.
Purpose of the Study:
- To develop and evaluate novel mRNA-based vaccine candidates targeting the rotavirus VP8* protein for parenteral administration.
- To compare the immunogenicity and efficacy of two distinct mRNA designs: monomeric P2-VP8* and nanoparticle-forming LS-P2-VP8*.
- To assess the potential of a trivalent nanoparticle-based mRNA vaccine against prevalent rotavirus P genotypes.
Main Methods:
- Designed and synthesized mRNA constructs encoding monomeric P2-VP8* and nanoparticle-forming LS-P2-VP8*.
- Utilized cryo-electron microscopy and western blotting to characterize protein expression, secretion, and self-assembly into nanoparticles.
- Assessed immunogenicity in rodent models, measuring both humoral (antibody) and cellular immune responses.
- Evaluated humoral responses in guinea pigs using monovalent and trivalent vaccine formulations against common P genotypes.
Main Results:
- Proteins derived from LS-P2-VP8* mRNA were secreted in vitro and self-assembled into 60-mer nanoparticles displaying VP8*.
- mRNA-encoded VP8* demonstrated immunogenicity in rodents, eliciting both humoral and cellular immune responses.
- The LS-P2-VP8* vaccine induced superior humoral responses compared to P2-VP8* in guinea pigs.
- Trivalent LS-P2-VP8* formulations showed encouraging immune responses against prevalent rotavirus P genotypes.
Conclusions:
- The LS-P2-VP8* mRNA construct effectively produces self-assembling nanoparticles displaying rotavirus VP8*.
- mRNA-based VP8* vaccines are immunogenic, inducing both humoral and cellular immunity.
- The trivalent LS-P2-VP8* nanoparticle vaccine represents a promising next-generation candidate for parenteral rotavirus immunization.
