Home » Key Scientific Articles » Intranasal P particle vaccine provided partial cross-variant protection against human GII.4 norovirus diarrhea in gnotobiotic pigs.

Intranasal P particle vaccine provided partial cross-variant protection against human GII.4 norovirus diarrhea in gnotobiotic pigs.

Kocher J1, Bui T1, Giri-Rachman E2, Wen K1, Li G1, Yang X1, Liu F1, Tan M3, Xia M4, Zhong W4, Jiang X5, Yuan L6.

J Virol. 2014;88(17):9728-43.

1Department of Biomedical Sciences and Pathobiology, Center for Molecular Medicine and Infectious Diseases, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA.

2Department of Biomedical Sciences and Pathobiology, Center for Molecular Medicine and Infectious Diseases, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA School of Life Science and Technology, Institut Teknologi, Bandung, Indonesia.

3Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.

4Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA.

5Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA University of Cincinnati College of Medicine, Cincinnati, Ohio, USA

6Department of Biomedical Sciences and Pathobiology, Center for Molecular Medicine and Infectious Diseases, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA.

 

Abstract

Noroviruses (NoVs) are the leading cause of nonbacterial acute gastroenteritis worldwide in people of all ages. The P particle is a novel vaccinecandidate 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 particlevaccine primed for stronger immune responses than VLPs, including significantly higher numbers of activated CD4+ T cells in all tissues, gamma interferon-producing (IFN-γ+) CD8+ T cells in the duodenum, regulatory T cells (Tregs) in the blood, and transforming growth factor {Beta} (TGF-β)-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.

IMPORTANCE:

The norovirus (NoV) P particle is a vaccine candidate derived from the protruding (P) domain of the NoV VP1 capsid protein. Pparticles 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 NoVdiarrhea 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.

Copyright © 2014, American Society for Microbiology. All Rights Reserved.

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Additional Information

Human noroviruses (NoVs) have become the leading cause of pediatric gastroenteritis since the development of rotavirus vaccines and is a major economic burden worldwide. NoV vaccine development has been limited by the lack of cell culture systems or small animal models to propagate virus for attenuated or inactivated vaccines. Additionally, there is a limited understanding of how NoV-induced immune responses correlate with protection. Recombinant capsid proteins, specifically virus-like particles (VLPs) and P particles, are potential vaccine candidates. VLPs are produced by expression of the full-length NoV capsid protein (VP1) in a eukaryotic expression system, while P particles are produced by expression of the VP1 protruding (P) domain in a prokaryotic expression system. The present study compares the protective efficacies and T cell immunogenicities of GII.4/VA387-derived VLPs and P particles to prior NoV infection in neonatal gnotobiotic pigs, which lack maternal antibodies and extraneous pathogens. Vaccines were given intranasally 3 times with chitosan and monophosphoryl lipid A adjuvants, while NoV-infected pigs received an oral dose of a GII.4/2006b variant. Vaccinated and infected pigs were challenged orally with the same NoV variant. Our protection data shows that prior infection with NoV (mimics natural infection) provides substantial, but not complete, protection from NoV-induced diarrhea and virus shedding. VLPs and P particles provided similar rates of protection from diarrhea (60.0% and 46.7%, respectively). Further, P particles increased the numbers of intestinal and systemic activated CD4+ T cells in all tissues and antiviral IFN-γ+CD8+ T cells in duodenum compared to VLPs.

Findings of this study have numerous implications. First, we demonstrated that prior NoV infection induces incomplete protection against diarrhea and shedding following re-infection. Second, we demonstrated cross-variant partial protection induced by both VLPs and P particles. Since NoVs undergo epochal evolution every 2-4 years and the vaccine and challenge NoV variants were collected 11 years apart, we showed NoV vaccines are capable of protecting against antigenically distinct variants. Further, we showed that both vaccines are able to provide similar protection rates as previously reported in humans. Third, we showed an inverse association between prechallenge regulatory T cells in duodenum and protection rates against diarrhea. Finally, we showed that P particles induce superior T cell responses to VLPs. This study indicates that P particles merit further investigation as a vaccine candidate against NoVs. P particles may be more economically viable than VLPs given their prokaryotic expression system and ability to present antigens from other pathogens.

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