Enhanced immune responses and protection by vaccination with respiratory syncytial virus fusion protein formulated with CpG oligodeoxynucleotide and innate defense regulator peptide in polyphosphazene microparticles
Enhanced immune responses and protection by vaccination with respiratory syncytial virus fusion protein formulated with CpG oligodeoxynucleotide and innate defense regulator peptide in polyphosphazene microparticles
复制标题
DOI：
10.1016/j.vaccine.2012.06.011
复制
发表时间：
2012-07-27
期刊：
影响因子：
5.5
通讯作者：
Littel-van den Hurk, S. van Drunen
中科院分区：
文献类型：
--
作者：
Garlapati, S.;Garg, R.;Littel-van den Hurk, S. van Drunen
尽管呼吸道合胞病毒 (RSV) 是儿童严重呼吸道疾病的主要原因，但迄今为止还没有可用的 RSV 疫苗。为了生产有效的亚单位疫苗，在哺乳动物细胞中表达截短的分泌型 F 蛋白 (Delta F)，进行纯化并显示形成三聚体。然后将 Delta F 蛋白与 CpG 寡脱氧核苷酸 (ODN) 和先天防御调节剂 (IDR) 肽一起配制在聚磷腈微粒 (Delta F-MP) 中。与仅用 Delta F 蛋白免疫的小鼠相比，用 Delta F-MP 肌内 (IM) 或鼻内 (IN) 免疫的小鼠在血清和肺部中产生了显着更高水平的病毒中和抗体，并且产生了更多数量的 IFN-γ 分泌细胞。相比之下，IM 递送的 Delta F 诱导大量 IL-5 产生，而 IN 递送的 Delta F 没有引发可测量的免疫反应。 RSV 攻击后，无论采用何种递送途径，在用 Delta F-MP 免疫的小鼠中基本上没有检测到病毒，也没有检测到免疫病理学证据。虽然仅用 Delta F 进行 IM 免疫的小鼠也表现出病毒复制减少，但它们的肺部 IgE、IL-4、IL-5、IL-13 和嗜酸性粒细胞趋化因子水平升高，并且在攻击后出现嗜酸性粒细胞增多。 IM 和 IN 递送后，Delta F-MP 制剂诱导的保护水平相同。 Delta F-MP 制剂的功效和安全性在棉鼠身上得到了证实，在接种 Delta F-MP 疫苗后，棉鼠也产生了增强的免疫反应，并完全免受 RSV 攻击。总之，应考虑将重组 Delta F 与 CpG ODN 和 IDR 肽一起配制在聚磷腈微粒中，以进一步评估其是否是安全有效的 RSV 疫苗。 (C) 2012 Elsevier Ltd. 保留所有权利。
Although respiratory syncytial virus (RSV) is the leading cause of serious respiratory tract disease in children, to date no RSV vaccine is available. To produce an effective subunit vaccine, a truncated secreted version of the F protein (Delta F) was expressed in mammalian cells, purified and shown to form trimers. The Delta F protein was then formulated with a CpG oligodeoxynucleotide (ODN) and an innate defense regulator (IDR) peptide in polyphosphazene microparticles (Delta F-MP). Mice immunized either intramuscularly (IM) or intranasally (IN) with Delta F-MP developed significantly higher levels of virus-neutralizing antibodies in the sera and lungs, as well as higher numbers of IFN-gamma secreting cells than mice immunized with the Delta F protein alone. In contrast, the IM delivered Delta F induced high production of IL-5 while the IN delivered Delta F did not elicit a measurable immune response. After RSV challenge, essentially no virus and no evidence of immunopathology were detected in mice immunized with Delta F-MP regardless of the route of delivery. While the mice immunized IM with Delta F alone also showed reduced virus replication, they developed enhanced levels of pulmonary IgE, IL-4, IL-5, IL-13 and eotaxin, as well as eosinophilia after challenge. The level of protection induced by the Delta F-MP formulation was equivalent after IM and IN delivery. The efficacy and safety of the Delta F-MP formulation was confirmed in cotton rats, which also developed enhanced immune responses and were fully protected from RSV challenge after vaccination with Delta F-MP. In conclusion, formulation of recombinant Delta F with CpG ODN and IDR peptide in polyphosphazene microparticles should be considered for further evaluation as a safe and effective vaccine against RSV. (C) 2012 Elsevier Ltd. All rights reserved.