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 VLPs against NoV infection and disease and the T cell responses to these treatments. Pigs were intranasally vaccinated with GII.4/1997 NoV (VA387)-derived P particles or virus-like particles (VLPs) or orally inoculated with a GII.4/2006b NoV variant. At post-inoculation day (PID) 28, pigs were euthanized or challenged with the GII.4/2006b variant and monitored... More
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 VLPs against NoV infection and disease and the T cell responses to these treatments. Pigs were intranasally vaccinated with GII.4/1997 NoV (VA387)-derived P particles or virus-like particles (VLPs) or orally inoculated with a GII.4/2006b NoV variant. At post-inoculation day (PID) 28, pigs were euthanized or 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% against virus shedding, while 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 duodenum and positively correlated with T cell expansion in ileum and spleen. The P particle vaccine primed for stronger immune responses than VLPs, including significantly higher activated CD4+ T cells in all tissues, IFN-γ+CD8+ T cells in duodenum, regulatory T cells (Tregs) in blood, and TGF-β producing CD4+CD25-FoxP3+ Tregs in spleen post-challenge, indicating 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.IMPORTANCE: The norovirus (NoV) P particle is a vaccine candidate derived from protruding (P) domain of NoV VP1 capsid protein. P particles can be easily produced in E. coli at high yield, 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 using the gnotobiotic pig model. The cross-variant protective efficacy of the P particle vaccine was comparable to that of the virus-like particle (VLP) vaccine in pigs (60%) and the homologous protective efficacy 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 has promise to reduce the disease burden and mortality.
