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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.

ABSTRACT: We inoculated gnotobiotic pigs orally/intranasally with human norovirus GII.4 HS66 strain virus-like particles (VLP) and immunostimulating complexes (ISCOM) or mutant E. coli LT toxin (mLT, R192G) as mucosal adjuvants, then assessed intestinal and systemic antibody and cytokine responses and homologous protection. Both vaccines induced high rates of seroconversion (100%) and coproconversion (75-100%). The VLP+mLT vaccine induced Th1/Th2 serum cytokines and cytokine secreting cells, whereas the VLP+ISCOM vaccine induced Th2 biased responses with significantly elevated IgM, IgA and IgG antibody-secreting cells in intestine. Nevertheless, both vaccines induced increased protection rates against viral shedding and diarrhea (75-100%) compared to controls; however, only 57% of controls shed virus.

SUBMITTER: Souza M

PROVIDER: S-EPMC4094375 | biostudies-literature | 2007 Dec

REPOSITORIES: biostudies-literature

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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.

Souza Menira M Costantini Veronica V Azevedo Marli S P MS Saif Linda J LJ

Vaccine 20071005 50

We inoculated gnotobiotic pigs orally/intranasally with human norovirus GII.4 HS66 strain virus-like particles (VLP) and immunostimulating complexes (ISCOM) or mutant E. coli LT toxin (mLT, R192G) as mucosal adjuvants, then assessed intestinal and systemic antibody and cytokine responses and homologous protection. Both vaccines induced high rates of seroconversion (100%) and coproconversion (75-100%). The VLP+mLT vaccine induced Th1/Th2 serum cytokines and cytokine secreting cells, whereas the V ...[more]

PMID: 18022293

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Project description:Noroviruses (NoVs) are the leading cause of nonbacterial acute gastroenteritis worldwide in people of all ages. The P particle is a novel vaccine candidate derived from the protruding (P) domain of the NoV VP1 capsid protein. This study utilized the neonatal gnotobiotic pig model to evaluate the protective efficacies of primary infection, P particles, and virus-like particles (VLPs) against NoV infection and disease and the T cell responses to these treatments. Pigs either were vaccinated intranasally with GII.4/1997 NoV (VA387)-derived P particles or VLPs or were inoculated orally with a GII.4/2006b NoV variant. At postinoculation day (PID) 28, pigs either were euthanized or were challenged with the GII.4/2006b variant and monitored for diarrhea and virus shedding for 7 days. The T cell responses in intestinal and systemic lymphoid tissues were examined. Primary NoV infection provided 83% homologous protection against diarrhea and 49% homologous protection against virus shedding, while the P particle and VLP vaccines provided cross-variant protection (47% and 60%, respectively) against diarrhea. The protection rates against diarrhea are significantly inversely correlated with T cell expansion in the duodenum and are positively correlated with T cell expansion in the ileum and spleen. The P particle vaccine primed for stronger immune responses than VLPs, including significantly higher numbers of activated CD4+ T cells in all tissues, gamma interferon-producing (IFN-?+) CD8+ T cells in the duodenum, regulatory T cells (Tregs) in the blood, and transforming growth factor ? (TGF-?)-producing CD4+ CD25- FoxP3+ Tregs in the spleen postchallenge, indicating that P particles are more immunogenic than VLPs at the same dose. In conclusion, the P particle vaccine is a promising vaccine candidate worthy of further development.The norovirus (NoV) P particle is a vaccine candidate derived from the protruding (P) domain of the NoV VP1 capsid protein. P particles can be easily produced in Escherichia coli at high yields and thus may be more economically viable than the virus-like particle (VLP) vaccine. This study demonstrated, for the first time, the cross-variant protection (46.7%) of the intranasal P particle vaccine against human NoV diarrhea and revealed in detail the intestinal and systemic T cell responses by using the gnotobiotic pig model. The cross-variant protective efficacy of the P particle vaccine was comparable to that of the VLP vaccine in pigs (60%) and to the homologous protective efficacy of the VLP vaccine in humans (47%). NoV is now the leading cause of pediatric dehydrating diarrhea, responsible for approximately 1 million hospital visits for U.S. children and 218,000 deaths in developing countries. The P particle vaccine holds promise for reducing the disease burden and mortality.

Dataset Information

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.

Publications

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.

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