Kocher Jacob, Bui Tammy, Giri-Rachman Ernawati, Wen Ke, Li Guohua, Yang Xingdong, Liu Fangning, Tan Ming, Xia Ming, Zhong Weiming, Jiang Xi, Yuan Lijuan
Department 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.
Department 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.
J Virol. 2014 Sep 1;88(17):9728-43. doi: 10.1128/JVI.01249-14. Epub 2014 Jun 11.
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-γ+) CD8+ T cells in the duodenum, regulatory T cells (Tregs) in the blood, and transforming growth factor β (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.
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.
诺如病毒（NoV）是全球各年龄段人群非细菌性急性胃肠炎的主要病因。P颗粒是一种新型疫苗候选物，源自NoV VP1衣壳蛋白的突出（P）结构域。本研究利用新生无菌猪模型评估初次感染、P颗粒和病毒样颗粒（VLP）对NoV感染和疾病的保护效力以及对这些治疗的T细胞反应。猪通过鼻内接种GII.4/1997 NoV（VA387）衍生的P颗粒或VLP，或通过口服接种GII.4/2006b NoV变体。在接种后第28天（PID 28），猪要么被安乐死，要么用GII.4/2006b变体进行攻毒，并监测腹泻和病毒排泄7天。检测肠道和全身淋巴组织中的T细胞反应。初次NoV感染提供了83%的同源性腹泻保护和49%的同源性病毒排泄保护，而P颗粒和VLP疫苗提供了针对腹泻的交叉变体保护（分别为47%和60%）。腹泻保护率与十二指肠中的T细胞扩增呈显著负相关，与回肠和脾脏中的T细胞扩增呈正相关。P颗粒疫苗引发的免疫反应比VLP更强，包括所有组织中活化CD4+ T细胞数量显著增加、十二指肠中产生γ干扰素的（IFN-γ+）CD8+ T细胞、血液中的调节性T细胞（Treg）以及攻毒后脾脏中产生转化生长因子β（TGF-β）的CD4+ CD25- FoxP3+ Treg，表明相同剂量下P颗粒比VLP更具免疫原性。总之，P颗粒疫苗是一种有前景的疫苗候选物，值得进一步开发。
诺如病毒（NoV）P颗粒是一种源自NoV VP1衣壳蛋白突出（P）结构域的疫苗候选物。P颗粒可以在大肠杆菌中高产率生产，因此可能比病毒样颗粒（VLP）疫苗在经济上更可行。本研究首次证明鼻内P颗粒疫苗对人类NoV腹泻的交叉变体保护（46.7%），并利用无菌猪模型详细揭示了肠道和全身T细胞反应。P颗粒疫苗的交叉变体保护效力与猪中VLP疫苗的效力（60%）相当，与人类中VLP疫苗的同源性保护效力（47%）相当。NoV现在是儿童脱水腹泻的主要病因，导致美国约100万儿童住院就诊，在发展中国家导致21.8万人死亡。P颗粒疫苗有望减轻疾病负担和降低死亡率。
