{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T09:40:31Z","timestamp":1769506831293,"version":"3.49.0"},"reference-count":39,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2019,3,2]],"date-time":"2019-03-02T00:00:00Z","timestamp":1551484800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["AI12366"],"award-info":[{"award-number":["AI12366"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Human noroviruses (HuNoVs) are responsible for more than 95% of the non-bacterial acute gastroenteritis epidemics in the world. The CDC estimates that every year 21 million individuals suffer from HuNoV-induced gastroenteritis in the United States. Currently, there is no FDA-approved vaccine for HuNoVs. Development of an effective vaccine has been hampered by the lack of an efficient cell culture system for HuNoVs and a suitable small animal model for pathogenesis study. In this study, we developed lactic acid bacteria (LAB) as a vector to deliver HuNoV antigen. A LAB strain (Lactococcus lactis) carrying VP1 gene of a HuNoV GII.4 virus (LAB-VP1) was constructed. It was found that HuNoV VP1 protein was highly expressed by LAB vector and was secreted into media supernatants. To test whether LAB-based HuNoV vaccine candidate is immunogenic, 4-day-old gnotobiotic piglets were orally inoculated with various doses of LAB-VP1. It was found that LABs were persistent in the small intestine of piglets and shed in pig feces for at least 25 days post inoculation. LAB DNA and VP1 were detected in mesenteric lymph nodes and spleen tissue in LAB-VP1 inoculated groups. HuNoV-specific IgG and IgA were detectable in serum and feces respectively at day 13 post-inoculation, and further increased at later time points. After being challenged with HuNoV GII.4 strain, a large amount of HuNoV antigens were observed in the duodenum, jejunum, and ileum sections of the intestine in the LAB control group. In contrast, significantly less, or no, HuNoV antigens were detected in the LAB-VP1 immunized groups. Collectively, these results demonstrate that a LAB-based HuNoV vaccine induces protective immunity in gnotobiotic piglets.<\/jats:p>","DOI":"10.3390\/v11030213","type":"journal-article","created":{"date-parts":[[2019,3,4]],"date-time":"2019-03-04T05:45:36Z","timestamp":1551678336000},"page":"213","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["A Lactic Acid Bacteria (LAB)-Based Vaccine Candidate for Human Norovirus"],"prefix":"10.3390","volume":"11","author":[{"given":"Kelsey","family":"Craig","sequence":"first","affiliation":[{"name":"Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xianjun","family":"Dai","sequence":"additional","affiliation":[{"name":"Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anzhong","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4438-980X","authenticated-orcid":false,"given":"Mijia","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miaoge","family":"Xue","sequence":"additional","affiliation":[{"name":"Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lucia","family":"Rosas","sequence":"additional","affiliation":[{"name":"Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas Z.","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew","family":"Niehaus","sequence":"additional","affiliation":[{"name":"Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryan","family":"Jennings","sequence":"additional","affiliation":[{"name":"Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianrong","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,3,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1097\/01.qco.0000244053.69253.3d","article-title":"Noroviruses everywhere: Has something changed?","volume":"19","author":"Estes","year":"2006","journal-title":"Curr. Opin. Infect. Dis."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Bartsch, S.M., Lopman, B.A., Ozawa, S., Hall, A.J., and Lee, B.Y. (2016). Global economic burden of norovirus gastroenteritis. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0151219"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"724","DOI":"10.1111\/1469-0691.12722","article-title":"The burden of norovirus gastroenteritis: An important foodborne and healthcare-related infection","volume":"20","author":"Belliot","year":"2014","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1240","DOI":"10.1016\/S0140-6736(94)92146-6","article-title":"Small round structured viruses: Airborne transmission and hospital control","volume":"343","author":"Caul","year":"1994","journal-title":"Lancet"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1111\/j.1600-065X.2008.00680.x","article-title":"Norovirus pathogenesis: Mechanisms of persistence and immune evasion in human populations","volume":"225","author":"Donaldson","year":"2008","journal-title":"Immunol. Rev."},{"key":"ref_6","unstructured":"NIAID (2018, March 07). NIAID Emerging Infectious Diseases\/Pathogens|NIH: National Institute Of Allergy And Infectious Diseases, Available online: https:\/\/www.niaid.nih.gov\/research\/emerging-infectious-diseases-pathogens."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1128\/JVI.72.2.1345-1353.1998","article-title":"Oral immunization with recombinant norwalk virus-like particles induces a systemic and mucosal immune response in mice","volume":"72","author":"Ball","year":"1998","journal-title":"J. Virol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1073\/pnas.1014577107","article-title":"Chimpanzees as an animal model for human norovirus infection and vaccine development","volume":"108","author":"Bok","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"6527","DOI":"10.1128\/jvi.66.11.6527-6532.1992","article-title":"Expression, self-assembly, and antigenicity of the norwalk virus capsid protein","volume":"66","author":"Jiang","year":"1992","journal-title":"J. Virol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"8448","DOI":"10.1016\/j.vaccine.2007.09.040","article-title":"A human norovirus-like particle vaccine adjuvanted with iscom or mlt induces cytokine and antibody responses and protection to the homologous GII.4 human norovirus in a gnotobiotic pig disease model","volume":"25","author":"Souza","year":"2007","journal-title":"Vaccine"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/S0016-5085(99)70548-2","article-title":"Recombinant norwalk virus-like particles given orally to volunteers: Phase i study","volume":"117","author":"Ball","year":"1999","journal-title":"Gastroenterology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2178","DOI":"10.1056\/NEJMoa1101245","article-title":"Norovirus vaccine against experimental human norwalk virus illness","volume":"365","author":"Atmar","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"870","DOI":"10.1093\/infdis\/jiu497","article-title":"Norovirus vaccine against experimental human gii.4 virus illness: A challenge study in healthy adults","volume":"211","author":"Bernstein","year":"2015","journal-title":"J. Infect. Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1016\/j.vaccine.2007.11.039","article-title":"Intranasal administration of a recombinant adenovirus expressing the norovirus capsid protein stimulates specific humoral, mucosal, and cellular immune responses in mice","volume":"26","author":"Guo","year":"2008","journal-title":"Vaccine"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1128\/JVI.76.2.730-742.2002","article-title":"Systemic, mucosal, and heterotypic immune induction in mice inoculated with venezuelan equine encephalitis replicons expressing norwalk virus-like particles","volume":"76","author":"Harrington","year":"2002","journal-title":"J. Virol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"9718","DOI":"10.1128\/JVI.01570-14","article-title":"Newcastle disease virus vector producing human norovirus-like particles induces serum, cellular, and mucosal immune responses in mice","volume":"88","author":"Kim","year":"2014","journal-title":"J. Virol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2942","DOI":"10.1128\/JVI.02332-10","article-title":"Vesicular stomatitis virus as a vector to deliver virus-like particles of human norovirus: A new vaccine candidate against an important noncultivable virus","volume":"85","author":"Ma","year":"2011","journal-title":"J. Virol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1126\/science.1257147","article-title":"Enteric bacteria promote human and mouse norovirus infection of b cells","volume":"346","author":"Jones","year":"2014","journal-title":"Science"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"25017","DOI":"10.1038\/srep25017","article-title":"Enterobacter cloacae inhibits human norovirus infectivity in gnotobiotic pigs","volume":"6","author":"Lei","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1387","DOI":"10.1126\/science.aaf5211","article-title":"Replication of human noroviruses in stem cell-derived human enteroids","volume":"353","author":"Ettayebi","year":"2016","journal-title":"Science"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1186\/1475-2859-12-32","article-title":"Oral immunization with lactococcus lactis secreting attenuated recombinant staphylococcal enterotoxin b induces a protective immune response in a murine model","volume":"12","author":"Asensi","year":"2013","journal-title":"Microb. Cell Fact."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.vaccine.2011.10.026","article-title":"Mucosal co-immunization of mice with recombinant lactococci secreting vapa antigen and leptin elicits a protective immune response against rhodococcus equi infection","volume":"30","author":"Cauchard","year":"2011","journal-title":"Vaccine"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"4775","DOI":"10.4049\/jimmunol.155.10.4775","article-title":"Induction of cell-mediated immune responses to human immunodeficiency virus type 1 gag protein by using listeria monocytogenes as a live vaccine vector","volume":"155","author":"Frankel","year":"1995","journal-title":"J. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1086\/509807","article-title":"Mucosal delivery of a pneumococcal vaccine using lactococcus lactis affords protection against respiratory infection","volume":"195","author":"Hanniffy","year":"2007","journal-title":"J. Infect. Dis."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3141","DOI":"10.1128\/AEM.68.6.3141-3146.2002","article-title":"Controlled production of stable heterologous proteins in lactococcus lactis","volume":"68","author":"Miyoshi","year":"2002","journal-title":"Appl. Environ. Microbiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1038\/nbt0797-653","article-title":"Oral vaccination of mice against tetanus with recombinant lactococcus lactis","volume":"15","author":"Robinson","year":"1997","journal-title":"Nat. Biotechnol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jviromet.2008.02.014","article-title":"Expression of the capsid protein of porcine circovirus type 2 in lactococcus lactis for oral vaccination","volume":"150","author":"Wang","year":"2008","journal-title":"J. Virol. Methods"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3535","DOI":"10.1128\/JVI.01306-06","article-title":"Binding patterns of human norovirus-like particles to buccal and intestinal tissues of gnotobiotic pigs in relation to A\/H histo-blood group antigen expression","volume":"81","author":"Cheetham","year":"2007","journal-title":"J. Virol."},{"key":"ref_29","first-page":"163","article-title":"A new strategy for vaccination","volume":"9","author":"Azizpour","year":"2017","journal-title":"Avicenna. J. Med. Biotechnol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"5691","DOI":"10.1007\/s00253-016-7557-x","article-title":"Lactic acid bacteria as mucosal delivery vehicles: A realistic therapeutic option","volume":"100","author":"Wang","year":"2016","journal-title":"Appl. Microbiol. Biotechnol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.ijfoodmicro.2010.06.022","article-title":"Microencapsulation of a probiotic and prebiotic in alginate-chitosan capsules improves survival in simulated gastro-intestinal conditions","volume":"142","author":"Ares","year":"2010","journal-title":"Int. J. Food Microbiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1139\/w03-092","article-title":"Survival of lactococci during passage through mouse digestive tract","volume":"49","author":"Kimoto","year":"2003","journal-title":"Can. J. Microbiol."},{"key":"ref_33","first-page":"696","article-title":"Use of mouse models to evaluate the persistence, safety, and immune modulation capacities of lactic acid bacteria","volume":"10","author":"Pavan","year":"2003","journal-title":"Clin. Diagn. Lab. Immunol."},{"key":"ref_34","first-page":"293","article-title":"Administration of oral probiotic bacteria to pregnant women causes temporary infantile colonization","volume":"38","author":"Schultz","year":"2004","journal-title":"J. Pediatr. Gastroenterol. Nutr."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1097\/QCO.0000000000000476","article-title":"Human noroviruses: Recent advances in a 50-year history","volume":"31","author":"Atmar","year":"2018","journal-title":"Curr. Opin. Infect. Dis."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1097\/MOG.0000000000000022","article-title":"Epidemiology of human noroviruses and updates on vaccine development","volume":"30","author":"Ramani","year":"2014","journal-title":"Curr. Opin. Gastroenterol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.4014\/jmb.1512.12002","article-title":"Lactic acid bacteria improves peyer\u2019s patch cell-mediated immunoglobulin a and tight-junction expression in a destructed gut microbial environment","volume":"26","author":"Kim","year":"2016","journal-title":"J. Microbiol. Biotechnol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"6679","DOI":"10.1128\/AEM.01566-15","article-title":"A gnotobiotic pig model for determining human norovirus inactivation by high-pressure processing","volume":"81","author":"Lou","year":"2015","journal-title":"Appl. Environ. Microbiol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"10372","DOI":"10.1128\/JVI.00809-06","article-title":"Pathogenesis of a genogroup ii human norovirus in gnotobiotic pigs","volume":"80","author":"Cheetham","year":"2006","journal-title":"J. Virol."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/11\/3\/213\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T12:35:51Z","timestamp":1760186151000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/11\/3\/213"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,3,2]]},"references-count":39,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2019,3]]}},"alternative-id":["v11030213"],"URL":"https:\/\/doi.org\/10.3390\/v11030213","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,3,2]]}}}