Isconova AB, Kungsgatan 109, SE-753 18 Uppsala, Sweden.
Vaccine. 2013 Mar 25;31(13):1725-33. doi: 10.1016/j.vaccine.2013.01.039. Epub 2013 Feb 4.
The novel saponin based adjuvant Matrix-M™ was recently used in a Phase I study of seasonal influenza in elderly. The present study is a pre-clinical evaluation of the efficacy and mode-of-action of Matrix-M™ formulated influenza vaccine in mice. A manuscript on safety profile and immunogenicity in elderly humans is under preparation. We have previously shown that subcutaneous injections of Matrix-M™, without coformulated antigen, results in a dose-dependent recruitment of leukocytes to draining lymph nodes (dLNs). Herein we compared the mode of action of Matrix-M™ with Alum, FCA and AS03 alone or formulated with influenza split virion antigen injected intramuscularly. The elicited responses in dLNs and spleen were investigated 48h later. Matrix-M™ was particularly efficient in activation of central innate immune cells such as neutrophils, DCs and macrophages compared to the other adjuvants analyzed. Moreover, the adjuvant influence on the recall immune response to influenza antigen was studied by in vitro re-stimulation of splenocytes from mice immunized with influenza antigen adjuvanted with Matrix-M™, Alum or AS03. Splenocytes from mice immunized with influenza antigen and Matrix-M™ produced both Th1 and Th2 cytokines upon re-stimulation. This response was significantly stronger than that induced by the other adjuvants studied. Interestingly, increased levels of the neutrophil chemoattractant KC were produced by antigen stimulated splenocytes from mice immunized with Matrix-M™ adjuvanted vaccine, which is in agreement with the increase of neutrophils into dLNs and spleen after Matrix-M™ injection. Furthermore, influenza antigen adjuvanted with Matrix-M™ induced significantly higher antigen-specific IgG1 and IgG2a responses compared to antigen alone. In conclusion, adjuvant Matrix-M™ activates the innate immune system without antigen present. This activation may explain the enhanced immunity to influenza seen with Matrix-M™ adjuvant. Despite this potent immune activation mediated by Matrix-M™, GLP-toxicity studies and clinical data suggest that Matrix-M™ adjuvant has a mild to moderate safety profile.
新型皂苷佐剂 Matrix-MTM 最近被用于老年人季节性流感的 I 期研究。本研究是对 Matrix-MTM 配方流感疫苗在小鼠中的功效和作用模式的临床前评估。关于老年人安全性和免疫原性的研究手稿正在准备中。我们之前已经表明，Matrix-MTM （不含佐剂抗原）的皮下注射会导致引流淋巴结（dLN）中白细胞的剂量依赖性募集。在此，我们比较了 Matrix-MTM 与铝佐剂、弗氏完全佐剂和 AS03 单独或与流感裂解病毒抗原混合肌肉注射的作用模式。48 小时后，研究了 dLN 和脾中的诱导反应。与其他分析的佐剂相比，Matrix-MTM 特别有效地激活了中性粒细胞、DC 和巨噬细胞等中枢固有免疫细胞。此外，通过体外刺激用 Matrix-MTM、铝佐剂或 AS03 佐剂免疫流感抗原的小鼠脾细胞，研究了佐剂对流感抗原回忆免疫反应的影响。用 Matrix-MTM 佐剂免疫的流感抗原的小鼠脾细胞在再刺激时产生 Th1 和 Th2 细胞因子。这种反应明显强于其他研究佐剂诱导的反应。有趣的是，用 Matrix-MTM 佐剂免疫的流感抗原刺激的脾细胞产生了更高水平的中性粒细胞趋化因子 KC，这与 Matrix-MTM 注射后 dLN 和脾中中性粒细胞的增加一致。此外，与单独抗原相比，用 Matrix-MTM 佐剂免疫的流感抗原诱导了显著更高的抗原特异性 IgG1 和 IgG2a 反应。总之，佐剂 Matrix-MTM 在没有抗原存在的情况下激活固有免疫系统。这种激活可能解释了 Matrix-MTM 佐剂增强的流感免疫力。尽管 Matrix-MTM 介导了这种有效的免疫激活，但 GLP 毒性研究和临床数据表明，Matrix-MTM 佐剂具有轻度至中度的安全性。
