Development of novel multivalent mucosal vaccines for human noroviruses

Human noroviruses (HuNoVs) account for more than 95% of non-bacterial acute gastroenteritis worldwide. Currently, there are no vaccines or antivirals against HuNoVs. This is due, in large part, to the lack of a robust cell culture system and a small animal challenge model. In general, live attenuated viral vaccines induce strong systemic and mucosal immunity and provide durable protection. However, it is not possible to generate a live attenuated vaccine for HuNoV because of its inefficient replication in vitro. In this situation, a live viral vectored vaccine platform represents a feasible strategy for development of a “live” HuNoV vaccine. Rotavirus (RV) vaccine (RotaTeq) and measles/mumps/rubella (MMR) vaccines are the two most successful live attenuated vaccines in human history, approved for use in children in 2006 and 1971, respectively. The goal of this project is to develop multivalent, live-vectored mucosal HuNoV vaccines using the FDA-approved RV and MMR vaccine platforms. We hypothesize that RV and MMR-based multivalent HuNoV vaccines will induce strong systemic and mucosal immune responses that confer broad protection against different HuNoV genogroups and genotypes. The major capsid (VP1) gene and protrusion (P) domain of VP1 gene of the most prevalent HuNoV genotype GII.4 and other important genotypes (e.g. GI.1, GII.1, GII.3, and GII.6) will be inserted into five re- assortant strains of the RotaTeq vaccine. RVs expressing VP1, P, double VP1, and double P will be generated and formulated into multivalent RV-NoV vaccines expressing 5-10 VP1 or P proteins. In parallel, these VP1, P, double VP1, and double P will be inserted into MeV, MuV-Jeryl Lynn 1 (JL1), and MuV-JL2 strains of the MMR vaccine, and multivalent MMR-NoV vaccines expressing 3-6 VP1 or P proteins will be generated. The immunogenicity of these multivalent RV-NoV and MMR-NoV vaccines will be screened in mice (for RV-NoV) and hamsters (for MMR-NoV). The two most immunogenic RV-NoV and MMR-NoV vaccine candidates will be chosen for oral (for RV-NoV) or intranasal (for MMR-NoV) immunization of gnotobiotic piglets, the only small animal challenge model for HuNoV. HuNoV-specific serum IgG, mucosal IgA, and their neutralization activities, gut- resident T cell immune responses, and their breadth will be characterized. The immunized gnotobiotic piglets will be orally challenged with different HuNoV genogroups and genotypes, and their protection efficacy will be determined. Finally, we will determine whether multivalent RV-NoV and MMR-NoV co-expressing VP1/P and T cell epitopes (such as nonstructural proteins NS1 and NS6) of HuNoV can enhance the immune responses and breadth of protection against HuNoV infection. Upon the completion of this project, we will have developed two mucosal multivalent HuNoV vaccines, the oral multivalent RV-NoV vaccine and the intranasal multivalent MMR- NoV vaccine that are safe, highly efficacious, and broadly protective. These vaccine candidates will directly lead to trials in non-human primates and humans. Project Number: 1R01AI183671-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Jianrong Li (+2 co-PIs) | Institution: OHIO STATE UNIVERSITY, Columbus, OH | Award Amount: $798,173 | Activity Code: R01 | Study Section: Special Emphasis Panel[ZRG1 DCAI-J (02)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01AI18367101A1