Nanoparticle Vaccines for Equine Rotavirus B

Novel equine rotavirus B (ERVB) was identified by this research group in collaboration with practitioners and breeding farms in outbreaks of severe neonatal diarrhea in the 2021 foaling season in central Kentucky. In the past 2022 foaling season, ERVB continued to cause severe diarrhea cases in neonatal foals. In addition to the welfare aspect of sick neonatal foals these outbreaks added a burden of stress and expense to farms, veterinarians and breeders. Additionally post-foaling mares confined with a sick foal can require mor intensive veterinary care to be successfully bred back (Dr Kristina Lu, personal communication). The virus has also been discovered in diseased foals in other states including New York, Pennsylvania, Maryland, and California. In addition, an outbreak consistent with ERVB-associated diarrhea in neonatal foals was noticed in a northerly county in Ireland. Recently, there is emerging evidence indicating that ERVB originated from ruminant (Goat Kids) and can shed from infected mares. In response to the immediate threat of ERVB to the equine industry, we propose to develop a safe and effective nanoparticle (NP) vaccine candidate that provides durable protection against ERVB infection in foals. Our central hypothesis is that the nanoparticle vaccine identified from our study elicits durable and high titer neutralizing antibodies in mares, and as a result, foals born to vaccinated mares will be protected against ERVB infection through the maternal colostral antibodies. We will utilize a three-pronged approach to address this hypothesis and achieve our goal. The first NP subunit vaccine expressing ERVB’s protective immunogens will be made and manufactured in insect cells through the baculovirus system. Numerous subunit vaccine products derived from this approach have been approved by the USDA. The second NP subunit vaccine will be produced in bacterial cells. We will investigate this simple and inexpensive bacteria-derived vaccine platform based on a recent report that a human rotavirus A subunit vaccine, expressed in Escherichia coli, is currently under phase III trials in children with a broad-spectrum protective efficacy against multiple strains of rotavirus A in children. Our NP subunit vaccines, made in bacterial and insect cells, will be based on the self-assembling ferritin nanoparticle platform because it can offer the advantage of multivalent antigen presentation. Ferritin nanoparticle vaccines can augment immunogenicity over monovalent subunit vaccines, which has been elegantly demonstrated in ferritin nanoparticle vaccines for human COVID-19, influenza, and other viruses. The third NP vaccine approach will focus on development of a mRNA-based subunit vaccine delivered by lipid nanoparticles. mRNA-based vaccines are highly effective against SARS-CoV-2 infection, which have been a primary driving force in controlling the COVID-19 pandemic over the past two years. Three NP vaccines will be examined and compared first in mice for stimulating durable high-titer neutralizing antibodies against ERVB. The vaccine candidate that results in the best in vitro neutralizing activity (potency and durability) in mice will be then evaluated in a pregnant mare vaccination/foal challenge study to further investigate its safety and protection against ERVB infection and disease in foals. Successful completion of the outlined objectives will lead to the development of an effective vaccine candidate capable of protecting foals against equine rotavirus B infection. This project will continue to leverage our unique resources in ERVB research ranging from well-documented clinical samples to antibody and diagnostic assays as well as full-genome sequencing capacity. Our resources also include an unique collection of reference ERVB antigens and antibodies and existing productive collaboration with the local equine industry. All these resources will accelerate our efforts to develop effective medical interventions to help combat the challenge to the equine industry by this serious emerging disease.