A Lactic Acid Bacteria (LAB)-Based Vaccine Candidate for Human Norovirus

Abstract

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.

Application of Recombinant Lactic Acid Bacteria (LAB) Live Vector Oral Vaccine in the Prevention of F4+ Enterotoxigenic Escherichia coli

“…Subsequently, they were separated from sow feeding and provided with artificial milk powder as their source of nutrition. The results reveal that after three rounds of immunization, significant weight gain was observed in the piglets along with elevated levels of serum IgG antibodies [ 49 ]. Furthermore, when exposed to a full dose of diarrhea, these immunized piglets demonstrated protection against it [ 50 ].…”

“…However, L. lactis was not found in the differential flora, indicating that L. lactis could not colonize the gastrointestinal tract for a long time. Relevant studies have shown that L. lactis can only survive for 4 h in the human gastrointestinal tract (GIT) [ 53 ], and when dead in the gastrointestinal tract, it cannot spread in the environment, which makes it safer as a genetically modified organism (GMO) [ 45 , 49 , 54 ].…”

Controlled Human Infection Models To Accelerate Vaccine Development

“…Despite considerable effort, the propagation of noroviruses by conventional cell culture techniques is not yet routine; however, efforts to overcome these obstacles are making progress (462)(463)(464)(465)(466). Human noroviruses do not infect other normal animal hosts; however, several studies with human norovirus conducted in gnotobiotic (germ-free) piglets suggest that vaccine candidates and probiotics can at least partially suppress clinical symptoms, viral replication, and shedding in these animals (467)(468)(469)(470).…”

Plasmid-Based Gene Expression Systems for Lactic Acid Bacteria: A Review

“…In the last decade, scientific interest has focused on the application of this group of food-grade bacteria as effective vehicles for mucosal delivery and for the delivery of recombinant prophylactic and therapeutic proteins, neutralizing antibodies, and the variable domain of heavy-chain-only antibodies from camelids-known as VHH antibodies or nanobodies-into the human gut, to prevent and treat inflammatory bowel diseases (IBDs), autoimmune disorders, infectious and non-infectious gastrointestinal diseases, and infections by pathogenic microorganisms from mucosal surfaces [18,[21][22][23][24][25][26]. As lactic acid bacteria (LAB) is a cell factory and delivery vehicle for the delivery of therapeutic proteins, an LAB strain (Lactococcus lactis) was used as a vector to deliver HuNoV (human noroviruses) antigen and it demonstrated that this LAB-based HuNoV vaccine induced protective immunity in gnotobiotic piglets [27].…”