Clausi Amber L, Morin Andrea, Carpenter John F, Randolph Theodore W
Department of Chemical and Biological Engineering, Center for Pharmaceutical Biotechnology, ECCH 111, Campus Box 424, University of Colorado, Boulder, Colorado 80309, USA.
J Pharm Sci. 2009 Jan;98(1):114-21. doi: 10.1002/jps.21433.
The mechanism(s) of the enhancement of the immune response by addition of aluminum salt adjuvants to parenterally administered protein-based vaccines is still the subject of debate. It has been hypothesized, however, that destabilization of the antigen structure on the surface of the adjuvant may be important for eliciting immune response. Also, it has been suggested that immune response to adjuvanted vaccines is reduced if the adjuvant particles become aggregated before administration because of processing steps such as freeze-drying. In this study, we tested these hypotheses and examined the immune response in a murine model to various liquid, freeze-dried, and spray freeze-dried formulations of a model vaccine, bovine intestinal alkaline phosphatase adsorbed on aluminum hydroxide. Enzymatic activity of the alkaline phosphatase was used as a sensitive indicator of intact native antigen structure. By manipulating the secondary drying temperature during lyophilization, vaccines were produced with varying levels of alkaline phosphatase enzymatic activity and varying degrees of adjuvant aggregation, as assessed by particle size distribution. Anti-alkaline phosphatase titers observed in immunized mice were independent of both the antigen's retained enzymatic activity and the vaccine formulation's mean particle diameter.
通过向肠胃外给药的蛋白质疫苗中添加铝盐佐剂来增强免疫反应的机制仍然是一个有争议的话题。然而，据推测，佐剂表面抗原结构的不稳定可能对引发免疫反应很重要。此外，有人提出，如果佐剂颗粒在给药前因冻干等加工步骤而聚集，那么对佐剂疫苗的免疫反应会降低。在本研究中，我们验证了这些假设，并在小鼠模型中检测了对一种模型疫苗（吸附在氢氧化铝上的牛肠碱性磷酸酶）的各种液体、冻干和喷雾冻干制剂的免疫反应。碱性磷酸酶的酶活性被用作完整天然抗原结构的敏感指标。通过在冻干过程中控制二次干燥温度，制备出了具有不同水平碱性磷酸酶酶活性和不同程度佐剂聚集的疫苗，佐剂聚集程度通过粒径分布进行评估。在免疫小鼠中观察到的抗碱性磷酸酶滴度与抗原保留的酶活性和疫苗制剂的平均粒径均无关。
