Potent immunity to low doses of influenza vaccine by probabilistic guided micro-targeted skin delivery in a mouse model.
Potent immunity to low doses of influenza vaccine by probabilistic guided micro-targeted skin delivery in a mouse model.
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DOI：
10.1371/journal.pone.0010266
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发表时间：
2010-04-21
期刊：
影响因子：
3.7
通讯作者：
Kendall MA
中科院分区：
文献类型：
--
作者：
Fernando GJ;Chen X;Prow TW;Crichton ML;Fairmaid EJ;Roberts MS;Frazer IH;Brown LE;Kendall MA
尽管广泛使用疫苗，每年仍有1 400多万人死于传染病。1853年发明的针和注射器仍然是主要的注射工具，将液体疫苗注射到肌肉中。如果将疫苗精确地送到皮肤表面下的狭窄层中，疫苗的效果可能会好得多，因为皮肤表面下含有密度高得多的强效抗原呈递细胞（apc），而apc是产生保护性免疫反应所必需的。我们假设成功的疫苗接种可以用远低于针和注射器所需的抗原剂量的方式实现。为了实现这一目标，使用基于概率的理论分析来靶向皮肤apc，我们设计了纳米贴片™，它包含一系列密集排列的投影（21025/cm2），人眼不可见（长度为110 μ m，逐渐变细，尖端锐度<1000 nm），用疫苗干燥涂覆并涂在皮肤上两分钟。在这里，我们展示了纳米贴片提供季节性流感疫苗（Fluvax®2008）直接接触数千个apc，与理论预测非常吻合。通过直接将疫苗物理靶向这些细胞，我们在小鼠中诱导出了保护水平的功能性抗体反应，并对流感病毒的攻击产生了保护作用，这与用针头和注射器肌肉注射的疫苗相当，但所递送的抗原不到所递送抗原的1/100。我们的研究结果表明，通过其他递送方法，不依赖于添加佐剂，只接种一次疫苗，注射剂量有了显著的改善——比其他报道的要大一个数量级。这项研究为扩展到人类研究提供了一个经过验证的数学/工程输送装置模板，我们推测，将这些发现成功地转化为人类，可以独特地帮助解决疫苗短缺和分发问题，同时减轻对针头的恐惧和对训练有素的从业人员管理疫苗的需求，例如在流感大流行期间。
Over 14 million people die each year from infectious diseases despite extensive vaccine use. The needle and syringe—first invented in 1853—is still the primary delivery device, injecting liquid vaccine into muscle. Vaccines could be far more effective if they were precisely delivered into the narrow layer just beneath the skin surface that contains a much higher density of potent antigen-presenting cells (APCs) essential to generate a protective immune response. We hypothesized that successful vaccination could be achieved this way with far lower antigen doses than required by the needle and syringe. To meet this objective, using a probability-based theoretical analysis for targeting skin APCs, we designed the Nanopatch™, which contains an array of densely packed projections (21025/cm2) invisible to the human eye (110 µm in length, tapering to tips with a sharpness of <1000 nm), that are dry-coated with vaccine and applied to the skin for two minutes. Here we show that the Nanopatches deliver a seasonal influenza vaccine (Fluvax® 2008) to directly contact thousands of APCs, in excellent agreement with theoretical prediction. By physically targeting vaccine directly to these cells we induced protective levels of functional antibody responses in mice and also protection against an influenza virus challenge that are comparable to the vaccine delivered intramuscularly with the needle and syringe—but with less than 1/100th of the delivered antigen. Our results represent a marked improvement—an order of magnitude greater than reported by others—for injected doses administered by other delivery methods, without reliance on an added adjuvant, and with only a single vaccination. This study provides a proven mathematical/engineering delivery device template for extension into human studies—and we speculate that successful translation of these findings into humans could uniquely assist with problems of vaccine shortages and distribution—together with alleviating fear of the needle and the need for trained practitioners to administer vaccine, e.g., during an influenza pandemic.
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影响因子：
5.5
作者：
FERNANDO, GJP;STENZEL, DJ;FRAZER, IH
通讯作者：
FRAZER, IH
影响因子：
64.8
作者：
Neumann, Gabriele;Noda, Takeshi;Kawaoka, Yoshihiro
通讯作者：
Kawaoka, Yoshihiro
DOI：
10.1038/nri1310
发表时间：
2004-03
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
Kupper TS;Fuhlbrigge RC
通讯作者：
Fuhlbrigge RC
影响因子：
6.5
作者：
Mulholland, William J.;Arbuthnott, Edward A. H.;Tirlapur, Uday K.
通讯作者：
Tirlapur, Uday K.
影响因子：
6.5
作者：
KOYAMA, Y;NAGAO, S;MARUNOUCHI, T
通讯作者：
MARUNOUCHI, T