Intranasal immunization with influenza VLPs incorporating membrane-anchored flagellin induces strong heterosubtypic protection.
Intranasal immunization with influenza VLPs incorporating membrane-anchored flagellin induces strong heterosubtypic protection.
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DOI：
10.1371/journal.pone.0013972
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发表时间：
2010-11-29
期刊：
影响因子：
3.7
通讯作者：
Compans RW
中科院分区：
文献类型：
--
作者：
Wang BZ;Xu R;Quan FS;Kang SM;Wang L;Compans RW
我们之前证明，将膜锚定形式的鞭毛蛋白掺入流感病毒样颗粒（VLP）中可显着提高VLP的免疫原性，通过肌内免疫诱导部分保护性异亚型免疫。由于粘膜疫苗的功效高度依赖于佐剂，并且对于预防流感等粘膜感染特别有效，因此我们通过粘膜免疫途径确定膜锚定鞭毛蛋白是否是VLP疫苗的有效佐剂。我们比较了膜锚定和可溶性鞭毛蛋白在小鼠模型中通过鼻内途径免疫 A/PR8 (H1N1) VLP 的佐剂作用。结果表明，膜锚定鞭毛蛋白是鼻内 (IN) 免疫的有效佐剂，可诱导增强的全身和粘膜抗体反应。当用病毒抗原刺激时，脾细胞培养物中细胞因子的产生也观察到了高细胞反应。所有用含鞭毛蛋白的VLP免疫的小鼠都在高致死剂量的同源病毒攻击以及高剂量异亚型病毒攻击（A/Philippine/82，H3N2的40 LD50）的攻击中存活下来。相比之下，标准 HA/M1 VLP 组在异亚型攻击后没有观察到保护作用。当通过粘膜途径与 VLP 共同给药时，可溶性鞭毛蛋白表现出中等的佐剂作用，增强的全身和粘膜反应以及部分异亚型保护表明了这一点。与抗原一起掺入流感 VLP 中的膜锚定形式的鞭毛蛋白可作为粘膜途径的佐剂，与标准 VLP 不同，用此类嵌合 VLP 进行免疫可引发保护性免疫，以抵抗远亲甲型流感病毒的攻击。
We demonstrated previously that the incorporation of a membrane-anchored form of flagellin into influenza virus-like particles (VLPs) improved the immunogenicity of VLPs significantly, inducing partially protective heterosubtypic immunity by intramuscular immunization. Because the efficacy of mucosal vaccination is highly dependent on an adjuvant, and is particularly effective for preventing mucosal infections such as influenza, we determined whether the membrane-anchored flagellin is an efficient adjuvant for VLP vaccines by a mucosal immunization route. We compared the adjuvant effect of membrane-anchored and soluble flagellins for immunization with influenza A/PR8 (H1N1) VLPs by the intranasal route in a mouse model. The results demonstrate that membrane-anchored flagellin is an effective adjuvant for intranasal (IN) immunization, inducing enhanced systemic and mucosal antibody responses. High cellular responses were also observed as shown by cytokine production in splenocyte cultures when stimulated with viral antigens. All mice immunized with flagellin-containing VLPs survived challenge with a high lethal dose of homologous virus as well as a high dose heterosubtypic virus challenge (40 LD50 of A/Philippines/82, H3N2). In contrast, no protection was observed with a standard HA/M1 VLP group upon heterosubtypic challenge. Soluble flagellin exhibited a moderate adjuvant effect when co-administered with VLPs by the mucosal route, as indicated by enhanced systemic and mucosal responses and partial heterosubtypic protection. The membrane-anchored form of flagellin incorporated together with antigen into influenza VLPs is effective as an adjuvant by the mucosal route and unlike standard VLPs, immunization with such chimeric VLPs elicits protective immunity to challenge with a distantly related influenza A virus.
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