Human norovirus (HuNoV) infections are responsible for more than 95% of the non-bacterial acute gastroenteritis worldwide and more than 60% of all food-borne illnesses in the US. Evidence suggests that HuNoVs and porcine norovirus (PoNoV) possess high zoonotic potential and, since PoNoV shares the highest identity to HuNoV GII strains, suggesting that swine may serve as reservoirs HuNoV and for emergence of novel HuNoVs and porcine/human GII recombinants. Despite the major efforts, vaccines or antiviral drugs are not available. This is due in major part to the lack of a cell culture system or a small animal model for HuNoV pathogenesis. The overall goal of this proposal is to develop a Lactococcus lactis or lactic acid bacteria (LAB) as the vector to deliver NoV virus-like particles (VLPs) and protrusion (P) particles, and to develop LAB-based live NoV vaccines for clinical trials. We have shown that LAB strains expressing VLP and P particles derived from HuNoV-GII.4 induced strong protective immune responses when orally inoculated into gnotobiotic (GN) piglets, the only nonprimate animal model that accurately replicates HuNoV disease. Using this unique animal model, we will determine the dynamics of LAB colonization and the expression, uptake of the NoV VLP and P particles in gastrointestinal tract, and innate immunity induced by LAB-based vaccines. We will determine if LAB- based vaccines provide protection against challenge with homologous (HuNoV-GII) or heterologous (PoNoV-GII) viruses. Subsequently, we will determine the mechanism by which LAB-based vaccine induces NoV-specific mucosal, humoral, and cellular immune responses, and define immune correlates of homologous and heterologous protection against NoV strains. Finally, we will determine if microencapsulation and a dendritic cell (DC) targeting peptide that specifically binds mucosal antigen- presenting cells (APCs) will enhance the immunogenicity of LAB-based NoV vaccines and will protect GN piglets from virulent virus challenge. Successful completion of these studies will result in development of safe, stable and efficacious vaccine(s) for the prevention of HuNoV/PoNoV gastroenteritis in humans and swine. This project will also provide a new avenue for vaccine development for other non-cultivable food- and water-borne viruses of human and domestic animal significance.

Public Health Relevance

Human norovirus (HuNoV) accounts for over 95% outbreaks of acute nonbacterial gastroenteritis worldwide and more than 60% of all food-borne illnesses in the US. Porcine norovirus (PoNoV) is a cause of nonbacterial diarrheal syndromes in swine. Currently, there is no vaccine or anti-viral drug for these viruses. The objective of this project s to develop a Lactococcus lactis or lactic acid bacteria (LAB) as a vector to deliver NoV virus-like particles (VLPs) and protrusion (P) particles, and to develop LAB- based NoV vaccines for prevention HuNoV and PoNoV in humans and pigs.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI123661-05
Application #
9872969
Study Section
Vaccines Against Microbial Diseases Study Section (VMD)
Program Officer
Alarcon, Rodolfo M
Project Start
2016-03-10
Project End
2021-02-28
Budget Start
2020-03-01
Budget End
2021-02-28
Support Year
5
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Ohio State University
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
Kim, Eunsoo; Lembert, Melanie; Fallata, Ghaith M et al. (2018) Intestinal Epithelial Cells Regulate Gut Eotaxin Responses and Severity of Allergy. Front Immunol 9:1692
Sun, Mingrui; Durkin, Patrick; Li, Jianrong et al. (2018) Label-Free On-Chip Selective Extraction of Cell-Aggregate-Laden Microcapsules from Oil into Aqueous Solution with Optical Sensor and Dielectrophoresis. ACS Sens 3:410-417
Yang, Zhihong; Chambers, Heather; DiCaprio, Erin et al. (2018) Internalization and dissemination of human norovirus and Tulane virus in fresh produce is plant dependent. Food Microbiol 69:25-32
Boyaka, Prosper N (2017) Inducing Mucosal IgA: A Challenge for Vaccine Adjuvants and Delivery Systems. J Immunol 199:9-16
He, Xiaoming (2017) Microscale Biomaterials with Bioinspired Complexity of Early Embryo Development and in the Ovary for Tissue Engineering and Regenerative Medicine. ACS Biomater Sci Eng 3:2692-2701
Zhang, Dongsheng; Tan, Ming; Zhong, Weiming et al. (2017) Human intestinal organoids express histo-blood group antigens, bind norovirus VLPs, and support limited norovirus replication. Sci Rep 7:12621
Wang, Hai; Agarwal, Pranay; Xiao, Yichao et al. (2017) A Nano-In-Micro System for Enhanced Stem Cell Therapy of Ischemic Diseases. ACS Cent Sci 3:875-885
Zhao, Shuting; Xu, Zhaobin; Wang, Hai et al. (2016) Bioengineering of injectable encapsulated aggregates of pluripotent stem cells for therapy of myocardial infarction. Nat Commun 7:13306
Lou, Fangfei; DiCaprio, Erin; Li, Xinhui et al. (2016) Variable High-Pressure-Processing Sensitivities for Genogroup II Human Noroviruses. Appl Environ Microbiol 82:6037-45
Zhao, Shuting; Zhang, Lingling; Han, Jianfeng et al. (2016) Conformal Nanoencapsulation of Allogeneic T Cells Mitigates Graft-versus-Host Disease and Retains Graft-versus-Leukemia Activity. ACS Nano 10:6189-200

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