Chimpanzees as an animal model for human norovirus infection and vaccine development
Chimpanzees as an animal model for human norovirus infection and vaccine development
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DOI：
10.1073/pnas.1014577107
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发表时间：
2011-01-04
影响因子：
11.1
通讯作者：
Green, Kim Y.
中科院分区：
文献类型：
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作者：
Bok, Karin;Parra, Gabriel I.;Green, Kim Y.
诺如病毒是急性胃肠炎的全球性病原体，但由于缺乏健全的动物模型，控制策略的制定受到阻碍。在黑猩猩身上的研究在几种挑剔的肝炎病毒的特征中发挥了关键作用，我们调查了对诺如病毒进行此类研究的可行性。注射人类诺瓦克病毒（NV）的血清阴性黑猩猩没有表现出胃肠炎的临床症状，但在粪便中病毒脱落的开始和持续时间以及血清抗体反应与在人类中观察到的相似。在肠道和肝脏活检中检测到NV RNA，同时在粪便中检测到病毒脱落，在小肠固有层细胞中观察到NV抗原的表达。两只被感染的黑猩猩在4个月、10个月或24个月后再次感染NV，它们对再次感染具有抵抗力，并且NV特异性血清抗体的存在与保护作用相关。我们评估了NV（基因组I， GI）和MD145（基因组II， GII）诺如病毒衍生的病毒样颗粒（VLPs）作为疫苗的免疫原性和有效性。在接种疫苗2个月和18个月后，肌肉注射GI VLPs的黑猩猩免受NV感染，而接种GII VLPs疫苗或安慰剂的黑猩猩则没有。本研究建立了黑猩猩作为研究诺如病毒复制和免疫的可行动物模型，并表明NV - VLP疫苗即使在较长时间后也能诱导保护性同源免疫。
Noroviruses are global agents of acute gastroenteritis, but the development of control strategies has been hampered by the absence of a robust animal model. Studies in chimpanzees have played a key role in the characterization of several fastidious hepatitis viruses, and we investigated the feasibility of such studies for the noroviruses. Seronegative chimpanzees inoculated i.v. with the human norovirus strain Norwalk virus (NV) did not show clinical signs of gastroenteritis, but the onset and duration of virus shedding in stool and serum antibody responses were similar to that observed in humans. NV RNA was detected in intestinal and liver biopsies concurrent with the detection of viral shedding in stool, and NV antigen expression was observed in cells of the small intestinal lamina propria. Two infected chimpanzees rechallenged 4, 10, or 24 mo later with NV were resistant to reinfection, and the presence of NV-specific serum antibodies correlated with protection. We evaluated the immunogenicity and efficacy of virus-like particles (VLPs) derived from NV (genogroup I, GI) and MD145 (genogroup II, GII) noroviruses as vaccines. Chimpanzees vaccinated intramuscularly with GI VLPs were protected from NV infection when challenged 2 and 18 mo after vaccination, whereas chimpanzees that received GII VLPs vaccine or a placebo were not. This study establishes the chimpanzee as a viable animal model for the study of norovirus replication and immunity, and shows that NV VLP vaccines could induce protective homologous immunity even after extended periods of time.