van der Kooij Renée S, Beukema Martin, Huckriede Anke L W, Zuidema Johan, Steendam Rob, Frijlink Henderik W, Hinrichs Wouter L J
Groningen Research Institute of Pharmacy, Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
Department of Medical Microbiology and Infection Prevention, University Medical Center Groningen, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
Pharmaceutics. 2023 Feb 16;15(2):676. doi: 10.3390/pharmaceutics15020676.
Although vaccination is still considered to be the cornerstone of public health care, the increase in vaccination coverage has stagnated for many diseases. Most of these vaccines require two or three doses to be administered across several months or years. Single-injection vaccine formulations are an effective method to overcome the logistical barrier to immunization that is posed by these multiple-injection schedules. Here, we developed subcutaneously (s.c.) injectable microspheres with a sustained release of the model antigen bovine serum albumin (BSA). The microspheres were composed of blends of two novel biodegradable multi-block copolymers consisting of amorphous, hydrophilic poly(ε-caprolactone)-poly(ethylene glycol)-poly(ε-caprolactone) (PCL-PEG-PCL) blocks and semi-crystalline poly(dioxanone) (PDO) blocks of different block sizes. In vitro studies demonstrated that the release of BSA could be tailored over a period of approximately four to nine weeks by changing the blend ratio of both polymers. Moreover, it was found that BSA remained structurally intact during release. Microspheres exhibiting sustained release of BSA for six weeks were selected for the in vivo study in mice. The induced BSA-specific IgG antibody titers increased up to four weeks after administration and were of the same magnitude as found in mice that received a priming and a booster dose of BSA in phosphate-buffered saline (PBS). Determination of the BSA concentration in plasma showed that in vivo release probably took place up to at least four weeks, although plasma concentrations peaked already one week after administration. The sustained-release microspheres might be a viable alternative to the conventional prime-boost immunization schedule, but a clinically relevant antigen should be incorporated to assess the full potential of these microspheres in practice.
尽管疫苗接种仍被视为公共卫生保健的基石，但许多疾病的疫苗接种覆盖率增长已停滞不前。大多数这类疫苗需要在几个月或几年内接种两剂或三剂。单针疫苗制剂是克服这些多针接种计划所带来的免疫后勤障碍的有效方法。在此，我们开发了可皮下注射的微球，其能持续释放模型抗原牛血清白蛋白（BSA）。这些微球由两种新型可生物降解多嵌段共聚物的混合物组成，这两种共聚物由无定形、亲水性的聚（ε-己内酯）-聚（乙二醇）-聚（ε-己内酯）（PCL-PEG-PCL）嵌段和不同嵌段大小的半结晶聚二氧六环酮（PDO）嵌段构成。体外研究表明，通过改变两种聚合物的混合比例，BSA的释放可在大约四到九周的时间内进行调整。此外，还发现BSA在释放过程中结构保持完整。选择了能持续释放BSA六周的微球用于小鼠体内研究。诱导产生的BSA特异性IgG抗体滴度在给药后四周内升高，且与在磷酸盐缓冲盐水（PBS）中接受BSA初免和加强剂量的小鼠中所发现的滴度相当。血浆中BSA浓度的测定表明，体内释放可能至少持续四周，尽管血浆浓度在给药后一周就已达到峰值。缓释微球可能是传统初免-加强免疫接种计划的一个可行替代方案，但应纳入一种临床相关抗原以评估这些微球在实际应用中的全部潜力。
