Didierlaurent Arnaud M, Morel Sandra, Lockman Laurence, Giannini Sandra L, Bisteau Michel, Carlsen Harald, Kielland Anders, Vosters Olivier, Vanderheyde Nathalie, Schiavetti Francesca, Larocque Daniel, Van Mechelen Marcelle, Garçon Nathalie
GlaxoSmithKline Biologicals, Rixensart, Belgium.
J Immunol. 2009 Nov 15;183(10):6186-97. doi: 10.4049/jimmunol.0901474. Epub 2009 Oct 28.
Adjuvant System 04 (AS04) combines the TLR4 agonist MPL (3-O-desacyl-4'-monophosphoryl lipid A) and aluminum salt. It is a new generation TLR-based adjuvant licensed for use in human vaccines. One of these vaccines, the human papillomavirus (HPV) vaccine Cervarix, is used in this study to elucidate the mechanism of action of AS04 in human cells and in mice. The adjuvant activity of AS04 was found to be strictly dependent on AS04 and the HPV Ags being injected at the same i.m. site within 24 h of each other. During this period, AS04 transiently induced local NF-kappaB activity and cytokine production. This led to an increased number of activated Ag-loaded dendritic cells and monocytes in the lymph node draining the injection site, which further increased the activation of Ag-specific T cells. AS04 was also found to directly stimulate those APCs in vitro but not directly stimulate CD4(+) T or B lymphocytes. These AS04-induced innate responses were primarily due to MPL. Aluminum salt appeared not to synergize with or inhibit MPL, but rather it prolonged the cytokine responses to MPL at the injection site. Altogether these results support a model in which the addition of MPL to aluminum salt enhances the vaccine response by rapidly triggering a local cytokine response leading to an optimal activation of APCs. The transient and confined nature of these responses provides further supporting evidence for the favorable safety profile of AS04 adjuvanted vaccines.
佐剂系统04（AS04）将Toll样受体4（TLR4）激动剂MPL（3 - O - 脱酰基 - 4'- 单磷酸脂A）与铝盐结合。它是一种新一代的基于TLR的佐剂，已获许可用于人类疫苗。在本研究中使用了其中一种疫苗——人乳头瘤病毒（HPV）疫苗希瑞适，以阐明AS04在人类细胞和小鼠中的作用机制。研究发现，AS04的佐剂活性严格依赖于AS04和HPV抗原在彼此24小时内于同一肌肉注射部位注射。在此期间，AS04短暂诱导局部核因子κB活性和细胞因子产生。这导致在注射部位引流的淋巴结中活化的载有抗原的树突状细胞和单核细胞数量增加，进而进一步增强了抗原特异性T细胞的活化。还发现AS04在体外可直接刺激这些抗原呈递细胞（APC），但不能直接刺激CD4(+) T细胞或B淋巴细胞。这些由AS04诱导的先天性反应主要归因于MPL。铝盐似乎既不与MPL协同作用也不抑制MPL，而是延长了注射部位对MPL的细胞因子反应。总之，这些结果支持了一个模型，即在铝盐中添加MPL可通过快速触发局部细胞因子反应来增强疫苗反应，从而导致APC的最佳活化。这些反应的短暂性和局限性为AS04佐剂疫苗良好的安全性提供了进一步的支持证据。
