Watanabe Izumi, Ross Ted M, Tamura Shin-ichi, Ichinohe Takeshi, Ito Satoshi, Takahashi Hidehiro, Sawa Hirofumi, Chiba Joe, Kurata Takeshi, Sata Tetsutaro, Hasegawa Hideki
Department of Pathology, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjyuku-ku, Tokyo 162-8640, Japan.
Vaccine. 2003 Nov 7;21(31):4532-8. doi: 10.1016/s0264-410x(03)00510-3.
For the induction of mucosal immune responses by intranasal vaccination, cholera toxin B subunits (CTB) and Escherichia coli heat-labile toxin (LT) are often administered as mucosal adjuvants in order to enhance immune responses to mucosally co-administered bystander antigens. However, these toxin also are the causative agents of diarrhea. There is a demand for the establishment of an effective and safer adjuvant or vaccine that elicits mucosal immunity, but does not require the use of CTB or LT adjuvants. In order to induce protective mucosal immune responses in the nasal area against influenza virus infection, we have examined the recombinant protein composed of the complement component, C3d, which is fused to the secreted form of hemagglutinin (sHA-mC3d3) in the influenza-BALB/c mouse model. The fusion protein sHA-mC3d3, the secretory form of hemagglutinin, and the transmembrane form of HA (tmHA) from the influenza virus were intranasally administered to the mice with or without CTB containing a trace amount of holotoxin (CTB*) as an adjuvant. After intranasal administration of these proteins with CTB*, all mice produced nasal IgA and serum IgG antibodies (Abs) against the viral HA. In addition, viral infection was completely inhibited in these mice. In contrast, in the absence of the adjuvant, only sHA-mC3d3-induced locally secreted IgA and serum IgG Abs and provided complete protection against the influenza virus challenge. Thus, C3d fused to the influenza HA antigen is an effective and safe tool for mucosal vaccination.
为通过鼻内接种诱导黏膜免疫反应，霍乱毒素B亚基（CTB）和大肠杆菌不耐热毒素（LT）常作为黏膜佐剂使用，以增强对黏膜共同接种的旁观者抗原的免疫反应。然而，这些毒素也是腹泻的病原体。因此，需要建立一种有效且更安全的佐剂或疫苗，能够引发黏膜免疫，但无需使用CTB或LT佐剂。为了在鼻腔区域诱导针对流感病毒感染的保护性黏膜免疫反应，我们在流感 - BALB/c小鼠模型中研究了由补体成分C3d组成的重组蛋白，该蛋白与血凝素的分泌形式（sHA - mC3d3）融合。将融合蛋白sHA - mC3d3、血凝素的分泌形式以及来自流感病毒的HA跨膜形式（tmHA），在有或没有含有微量全毒素（CTB*）作为佐剂的CTB的情况下，经鼻内给予小鼠。在与CTB*一起经鼻内给予这些蛋白后，所有小鼠均产生了针对病毒HA的鼻腔IgA和血清IgG抗体（Abs）。此外，这些小鼠中的病毒感染被完全抑制。相比之下，在没有佐剂的情况下，只有sHA - mC3d3诱导局部分泌的IgA和血清IgG Abs，并提供了针对流感病毒攻击的完全保护。因此，与流感HA抗原融合的C3d是用于黏膜疫苗接种的有效且安全的工具。
