A new intranasal influenza vaccine based on a novel polycationic lipid-ceramide carbamoyl-spermine (CCS). II. Studies in mice and ferrets and mechanism of adjuvanticity
A new intranasal influenza vaccine based on a novel polycationic lipid-ceramide carbamoyl-spermine (CCS). II. Studies in mice and ferrets and mechanism of adjuvanticity
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DOI：
10.1016/j.vaccine.2011.01.009
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发表时间：
2011-03-16
期刊：
影响因子：
5.5
通讯作者：
Barenholz, Yechezkel
中科院分区：
文献类型：
--
作者：
Even-Or, Orli;Joseph, Aviva;Barenholz, Yechezkel
我们最近表明，由新型聚阳离子鞘脂（神经酰胺氨基甲酰精胺，CCS）组成的脂质组装体与胆固醇（CCS/C）复合时，对于小鼠胃肠外和鼻内（i.n.）注射的流感疫苗和其他疫苗来说是一种有效的佐剂/载体。在这里，我们将这些研究扩展到雪貂，这是一种已建立的流感感染模型。我们还解决了为什么基于 CCS/C 的小鼠脂质体疫苗（也称为 VaxiSome (TM)）优于基于其他脂质成分（中性、阴离子或阳离子）脂质体的疫苗。与用未佐剂的流感疫苗肌肉注射免疫的雪貂相比，用CCS/C流感疫苗免疫的雪貂产生显着更高的血凝抑制（HI）抗体滴度，这表明基于CCS/C的疫苗具有很强的免疫原性。此外，i.n。根据体重减轻、体温升高和病毒滴度确定，在同源病毒攻击后，佐剂疫苗可显着降低雪貂流感病毒感染的严重程度。未观察到不良反应。注射后的药代动力学和生物分布研究在小鼠中施用基于 CCS/C 的疫苗表明，脂质和抗原在鼻和肺中保留至少 24 小时，并且这种保留似乎与佐剂疫苗制剂引起的优异免疫原性相关。 CCS脂质还增加细胞因子（主要是IFNγ、IL-2和IL-12）的产生和共刺激分子的表达，这可能进一步解释了这种基于脂质体的疫苗的强大佐剂作用。 (C) 2011 Elsevier Ltd. 保留所有权利。
We recently showed that lipid assemblies comprised of a novel polycationic sphingolipid (ceramide carbamoyl-spermine, CCS) are an effective adjuvant/carrier when complexed with cholesterol (CCS/C) for influenza and other vaccines administered parenterally and intranasally (i.n.) in mice. Here we expand these studies to ferrets, an established model of influenza infection. We also address the question of why the CCS/C-based liposomal vaccine (also known as VaxiSome (TM)) in mice is superior to vaccines based on liposomes of other lipid compositions (neutral, anionic or cationic). Ferrets immunized in. with CCS/C-influenza vaccine produced significantly higher hemagglutination inhibition (HI) antibody titers compared to ferrets immunized intramuscularly with the unadjuvanted influenza vaccine, indicating that the CCS/C-based vaccine is very immunogenic. Furthermore, the i.n. adjuvanted vaccine was shown to significantly reduce the severity of influenza virus infection in ferrets following homologous viral challenge as determined by weight loss, temperature rise and viral titer. No adverse reactions were observed. Pharmacokinetic and biodistribution studies following i.n. administration in mice of CCS/C-based vaccine showed that both the lipids and antigens are retained in the nose and lung for at least 24h, and it appears that this retention correlates with the superior immunogenicity elicited by the adjuvanted vaccine formulation. The CCS lipid also increases production of cytokines (mainly IFN gamma, IL-2 and IL-12) and co-stimulatory molecules' expression, which might further explain the robust adjuvantation of this liposome-based vaccine. (C) 2011 Elsevier Ltd. All rights reserved.