Johansson Jeannette, Hellman Lars
Department of Cell and Molecular Biology, Uppsala University, BMC, Box 596, 75124 Uppsala, Sweden.
Vaccine. 2007 Feb 19;25(9):1676-82. doi: 10.1016/j.vaccine.2006.10.055. Epub 2006 Nov 13.
Development of vaccines targeting important self-molecules like tumor antigens, IgE, cytokines or other regulatory molecules, brings about challenges that are not met in classical vaccine development. Tolerance inducing mechanisms reduce the levels of therapeutic antibodies in the vaccinated subject, and anti-self antibody titers are frequently more than 50-fold lower than the anti-non-self response to the carrier. In order to overcome this limitation in efficacy we have explored various methods to enhance the immunogenicity of the vaccine antigen. Vaccination with a molecule containing two IgE Cepsilon3 domains and thereby a low level of repetitiveness markedly increased the efficacy. The anti-IgE antibody titers in the animals treated with the dimeric vaccine antigen were 4.5, 5 and 8 times higher than in the animals treated with the monomer, in three independent experiments. In addition, this increase in efficacy was not masked by the use of potent adjuvants. The effect persisted even in the presence of Freunds or Montanide ISA 51, two mineral oil based adjuvants. This in contrast to most Toll-like receptor (TLR) agonists, which appear to enhance the immune response only when administrated together with weak adjuvants. This clearly shows that the introduction of a moderately repetitive structure is enough to substantially increase the efficacy of a therapeutic vaccine.
开发针对肿瘤抗原、IgE、细胞因子或其他调节分子等重要自身分子的疫苗，带来了传统疫苗开发中未曾遇到的挑战。诱导耐受的机制会降低接种疫苗个体体内治疗性抗体的水平，且抗自身抗体滴度通常比针对载体的抗非自身反应低50倍以上。为了克服这种疗效上的限制，我们探索了各种方法来增强疫苗抗原的免疫原性。接种含有两个IgE Cε3结构域且重复性较低的分子，显著提高了疗效。在三项独立实验中，用二聚体疫苗抗原处理的动物体内抗IgE抗体滴度比用单体处理的动物分别高4.5倍、5倍和8倍。此外，这种疗效的提高并未因使用强效佐剂而被掩盖。即使存在弗氏佐剂或Montanide ISA 51（两种基于矿物油的佐剂），这种效果依然存在。这与大多数 Toll样受体（TLR）激动剂形成对比，后者似乎只有在与弱佐剂一起使用时才会增强免疫反应。这清楚地表明，引入适度的重复结构足以显著提高治疗性疫苗的疗效。
