Microneedle-based vaccines.
Microneedle-based vaccines.
复制标题
DOI：
10.1007/978-3-540-92165-3_18
复制
发表时间：
2009
影响因子：
--
通讯作者：
Andrianov, Alexander K
中科院分区：
文献类型：
--
作者：
Prausnitz, Mark R;Mikszta, John A;Cormier, Michel;Andrianov, Alexander K
大流行性流感的威胁和其他公共卫生需求促使开发更好的疫苗输送系统。为了解决这一需求，微针已经被开发为使用低成本制造方法制造的微米级针，其使用可能适合于自我施用的简单装置将疫苗施用到皮肤中。使用实心或中空微针的递送可以通过以下方式实现：（i）刺穿皮肤，然后将疫苗制剂或贴剂施用到透化的皮肤上，（ii）将疫苗涂覆或包封到微针上或微针内以在皮肤中快速或延迟溶解和释放，以及（iii）使用改进的注射器或泵注射到皮肤中。天花、TB和其他疫苗的广泛临床经验表明，使用常规皮内注射将疫苗递送到皮肤中通常是安全和有效的，并且与肌内注射相比，通常以较低剂量激发相同的免疫应答。使用微针的动物实验也显示出类似的益处。针头已被用于向啮齿动物递送完整的灭活病毒、三价裂解抗原疫苗和编码流感血凝素的DNA质粒，并发现了强烈的抗体应答。此外，将抗黄热病的ChimeriVax™-JE施用于非人灵长类动物，产生的中和抗体的保护水平是皮下递送的7倍以上;将编码B型肝炎表面抗原的DNA质粒施用于小鼠，产生的抗体和T细胞应答至少与皮下注射一样强;将炭疽杆菌重组保护性抗原给予家兔，并以低于肌肉注射的剂量提供对致死性气溶胶炭疽孢子攻击的完全保护;将编码四种牛痘病毒基因的DNA质粒与电穿孔联合施用于小鼠，产生显然包括Th 1和Th 2应答的中和抗体。在具有模型疫苗卵清蛋白的小鼠中专门研究了使用微针的剂量节省。在低剂量（1 µg）下，微针的特异性抗体滴度比皮下注射高一个数量级，比肌内注射高两个数量级。在较高剂量下，所有递送方法的抗体应答均增加。在最高水平（20-80 µg）下，给药途径对免疫应答无显著影响。关于安全性，在人类和动物受试者中超过1000次微针插入中未观察到感染或其他严重不良事件。短微针（<1 mm）通常不会发生出血。经常观察到高度局部化、轻度和短暂的红斑。据报道，针刺疼痛为不存在至轻度，并且总是远低于皮下注射针对照。总体而言，这些研究表明，微针可以提供一种安全有效的方法来输送疫苗，并可能增加需要较低疫苗剂量的属性，允许低成本制造，并实现简单的分配和管理。
The threat of pandemic influenza and other public health needs motivates development of better vaccine delivery systems. To address this need, microneedles have been developed as micron-scale needles fabricated using low-cost manufacturing methods that administer vaccine into the skin using a simple device that may be suitable for self-administration. Delivery using solid or hollow microneedles can be accomplished by (i) piercing the skin and then applying a vaccine formulation or patch onto the permeabilized skin, (ii) coating or encapsulating vaccine onto or within microneedles for rapid, or delayed, dissolution and release in the skin and (iii) injection into the skin using a modified syringe or pump. Extensive clinical experience with smallpox, TB and other vaccines has shown that vaccine delivery into the skin using conventional intradermal injection is generally safe and effective and often elicits the same immune responses at lower doses compared to intramuscular injection. Animal experiments using microneedles have shown similar benefits. Microneedles have been used to deliver whole, inactivated virus; trivalent split antigen vaccines; and DNA plasmid encoding the influenza hemagglutinin to rodents and found strong antibody responses. In addition, ChimeriVax™-JE against yellow fever was administered to non-human primates and generated protective levels of neutralizing antibodies more than seven times greater than subcutaneous delivery; DNA plasmid encoding hepatitis B surface antigen was administered to mice and generated antibody and T cell responses at least as strong as hypodermic injections; recombinant Protective Antigen of Baccilus anthracis was administered to rabbits and provided complete protection from lethal aerosol anthrax spore challenge at a lower dose than intramuscular injection; and DNA plasmid encoding four vaccinia virus genes administered to mice in combination with electroporation generated neutralizing antibodies that apparently included both Th1 and Th2 responses. Dose sparing with microneedles was specifically studied in mice with the model vaccine ovalbumin. At low dose (1 µg), specific antibody titers from microneedles were one order of magnitude greater than subcutaneous injection and two orders of magnitude greater than intramuscular injection. At higher doses, antibody responses increased for all delivery methods. At the highest levels (20–80 µg), the route of administration had no significant effect on the immune response. Concerning safety, no infections or other serious adverse events have been observed in well over 1000 microneedle insertions in human and animal subjects. Bleeding generally does not occur for short microneedles (<1 mm). Highly localized, mild and transient erythema is often observed. Microneedle pain has been reported as non-existent to mild, and always much less than a hypodermic needle control. Overall, these studies suggest that microneedles may provide a safe and effective method to deliver vaccines with possible added attributes of requiring lower vaccines doses, permitting low-cost manufacturing, and enabling simple distribution and administration.