An Intranasally Delivered Toll-Like Receptor 7 Agonist Elicits Robust Systemic and Mucosal Responses to Norwalk Virus-Like Particles
An Intranasally Delivered Toll-Like Receptor 7 Agonist Elicits Robust Systemic and Mucosal Responses to Norwalk Virus-Like Particles
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DOI：
10.1128/cvi.00230-10
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发表时间：
2010-12-01
影响因子：
--
通讯作者：
Herbst-Kralovetz, Melissa M.
中科院分区：
文献类型：
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作者：
Velasquez, Lissette S.;Hjelm, Brooke E.;Herbst-Kralovetz, Melissa M.
诺瓦克病毒（NV）是来自诺如病毒属的肠道病原体，并且是人类非细菌性胃肠炎的主要原因。已知NV病毒样颗粒（VLP）经鼻递送时可引发全身和粘膜免疫应答;然而，免疫保护的相关性尚不清楚，与安全且具有免疫原性的粘膜佐剂共同递送可增强保护性抗NV免疫应答。瑞喹莫特（R848）是一种基于咪唑喹啉的Toll样受体7和/或8（TLR 7/8）激动剂，正在FDA批准的临床疫苗试验中作为佐剂进行评估。因此，我们评估了两种基于咪唑喹啉的TLR 7和TLR 7/8激动剂与植物来源的NV VLP鼻内共递送时的佐剂活性。我们还比较了这些激动剂的活性的金标准粘膜佐剂，霍乱毒素（CT）。我们的研究结果表明，与TLR 7激动剂，gardiquimod（GARD），共递送诱导NV VLP特异性血清IgG和IgG同种型反应和粘膜伊加反应，在胃肠道，呼吸道，生殖道，是上级的R848诱导和粘膜佐剂CT诱导的。本研究支持继续研究GARD作为NV VLP的粘膜佐剂，并可能用于其他基于VLP的疫苗，这些疫苗在远端粘膜部位（例如，例如，在一个实施例中，呼吸道和生殖道）。
Norwalk virus (NV) is an enteric pathogen from the genus Norovirus and a major cause of nonbacterial gastroenteritis in humans. NV virus-like particles (VLPs) are known to elicit systemic and mucosal immune responses when delivered nasally; however, the correlates of immune protection are unknown, and codelivery with a safe and immunogenic mucosal adjuvant may enhance protective anti-NV immune responses. Resiquimod (R848), an imidazoquinoline-based Toll-like receptor 7 and/or 8 (TLR7/8) agonist, is being evaluated as an adjuvant in FDA-approved clinical vaccine trials. As such, we evaluated the adjuvant activity of two imidazoquinoline-based TLR7 and TLR7/8 agonists when codelivered intranasally with plant-derived NV VLPs. We also compared the activity of these agonists to the gold standard mucosal adjuvant, cholera toxin (CT). Our results indicate that codelivery with the TLR7 agonist, gardiquimod (GARD), induces NV VLP-specific serum IgG and IgG isotype responses and mucosal IgA responses in the gastrointestinal, respiratory, and reproductive tracts that are superior to those induced by R848 and comparable to those induced by the mucosal adjuvant CT. This study supports the continued investigation of GARD as a mucosal adjuvant for NV VLPs and possible use for other VLP-based vaccines for which immune responses at distal mucosal sites (e. g., respiratory and reproductive tracts) are desired.