Clinical Vaccine R&D Center, Chonnam National University, Gwangju 500-757, Republic of Korea.
Vaccine. 2012 Jan 5;30(2):466-74. doi: 10.1016/j.vaccine.2011.10.058. Epub 2011 Oct 31.
The influenza virus, a mucosal pathogen that infects the respiratory tract, is a major global health issue. There have been attempts to mucosally administer inactivated influenza vaccines to induce both mucosal and systemic immune responses. However, mucosally administered inactivated influenza vaccine has low immunogenicity, which is partially due to the lack of an effective mucosal adjuvant. The development of a safe and effective mucosal adjuvant is a prerequisite to the practical use of a mucosal inactivated influenza vaccine. We have previously demonstrated that a bacterial flagellin, Vibrio vulnificus FlaB, when mixed with antigen and administered intranasally, exerts a strong mucosal adjuvant activity by stimulating the Toll-like receptor 5 (TLR5). In this study, we tested whether the FlaB protein could serve as an effective mucosal adjuvant for an inactivated trivalent influenza vaccine (TIV) manufactured for humans; in a murine vaccination model, this vaccine consists of A/Brisbane/59/07 (H1N1 subtype), A/Uruguay/716/07 (H3N2 subtype), and B/Florida/4/06 (B type). Intranasal co-administration of the TIV with FlaB induced prominent humoral responses as demonstrated by high influenza-specific IgA levels in both the mucosal secretions and serum and significant specific IgG induction in the systemic compartment. The FlaB protein significantly potentiated influenza-specific cytokine production by draining lymph node cells and splenocytes. The FlaB mucosal adjuvant conferred excellent protection against a lethal challenge with a live virulent virus with high hemagglutination inhibition (HAI) antibody (Ab) titers. The FlaB did not accumulate in the olfactory nerve and epithelium, guaranteeing against a retrograde uptake into the central nervous system. These results suggest that FlaB can be used as a promising mucosal adjuvant for nasal inactivated influenza vaccine development.
流感病毒是一种感染呼吸道的黏膜病原体，是一个全球性的重大健康问题。人们曾尝试经黏膜给予灭活流感疫苗以诱导黏膜和全身免疫应答。然而，经黏膜给予的灭活流感疫苗的免疫原性较低，部分原因是缺乏有效的黏膜佐剂。开发安全有效的黏膜佐剂是黏膜给予的灭活流感疫苗实际应用的前提。我们之前已经证明，当与抗原混合并经鼻腔给予时，一种细菌鞭毛蛋白，创伤弧菌 FlaB，通过刺激 Toll 样受体 5（TLR5）发挥强烈的黏膜佐剂活性。在这项研究中，我们测试了 FlaB 蛋白是否可以作为一种有效的黏膜佐剂用于人类制造的三价灭活流感疫苗（TIV）；在小鼠免疫接种模型中，该疫苗由 A/Brisbane/59/07（H1N1 亚型）、A/Uruguay/716/07（H3N2 亚型）和 B/Florida/4/06（B 型）组成。TIV 与 FlaB 经鼻腔共同给予可诱导明显的体液免疫应答，表现为黏膜分泌物和血清中流感特异性 IgA 水平升高，以及全身部位中显著的特异性 IgG 诱导。FlaB 蛋白显著增强了引流淋巴结细胞和脾细胞中流感特异性细胞因子的产生。FlaB 黏膜佐剂赋予了针对具有高血凝抑制（HAI）抗体（Ab）滴度的活毒致命攻击的优异保护作用。FlaB 不会在嗅神经和上皮中积累，从而保证不会逆行摄取到中枢神经系统。这些结果表明，FlaB 可用作鼻内灭活流感疫苗开发的有前途的黏膜佐剂。
