Depelsenaire Alexandra C I, Meliga Stefano C, McNeilly Celia L, Pearson Frances E, Coffey Jacob W, Haigh Oscar L, Flaim Christopher J, Frazer Ian H, Kendall Mark A F
D2G2, The Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, Queensland, Australia.
The University of Queensland, Diamantina Institute for Cancer, Brisbane, Queensland, Australia.
J Invest Dermatol. 2014 Sep;134(9):2361-2370. doi: 10.1038/jid.2014.174. Epub 2014 Apr 8.
Vaccines delivered to the skin by microneedles-with and without adjuvants-have increased immunogenicity with lower doses than standard vaccine delivery techniques such as intramuscular or intradermal injection. However, the mechanisms underlying this skin-mediated "adjuvant" effect are not clear. Here, we show that the dynamic application of a microprojection array (the Nanopatch) to skin generates localized transient stresses invoking cell death around each projection. Nanopatch application caused significantly higher levels (∼65-fold) of cell death in murine ear skin than i.d. injection using a hypodermic needle. Measured skin cell death is associated with modeled stresses ∼1-10 MPa. Nanopatch-immunized groups also yielded consistently higher anti-immunoglobulin G endpoint titers (up to 50-fold higher) than i.d. groups after delivery of a split virion influenza vaccine. Importantly, colocalization of cell death with nearby live skin cells and delivered antigen was necessary for immunogenicity enhancement. These results suggest a correlation between cell death caused by the Nanopatch with increased immunogenicity. We propose that the localized cell death serves as a "physical immune enhancer" for the adjacent viable skin cells, which also receive antigen from the projections. This natural immune enhancer effect has the potential to mitigate or replace chemical-based adjuvants in vaccines.
通过微针（有无佐剂）递送至皮肤的疫苗，与肌肉注射或皮内注射等标准疫苗递送技术相比，在较低剂量下具有更高的免疫原性。然而，这种皮肤介导的“佐剂”效应背后的机制尚不清楚。在这里，我们表明，将微针阵列（纳米贴片）动态应用于皮肤会产生局部瞬时应力，引发每个微针周围的细胞死亡。纳米贴片的应用在小鼠耳部皮肤中引起的细胞死亡水平比皮下注射皮下针高得多（约65倍）。测得的皮肤细胞死亡与模拟应力~1-10MPa相关。在递送裂解病毒流感疫苗后，纳米贴片免疫组产生的抗免疫球蛋白G终点滴度也始终高于皮内注射组（高达50倍）。重要的是，细胞死亡与附近活皮肤细胞和递送抗原的共定位是增强免疫原性所必需的。这些结果表明纳米贴片引起的细胞死亡与免疫原性增加之间存在相关性。我们提出，局部细胞死亡作为相邻活皮肤细胞的“物理免疫增强剂”，这些活皮肤细胞也从微针接收抗原。这种天然免疫增强剂效应有可能减轻或替代疫苗中基于化学的佐剂。
