Functional testing of an inhalable nanoparticle based influenza vaccine using a human precision cut lung slice technique.
Functional testing of an inhalable nanoparticle based influenza vaccine using a human precision cut lung slice technique.
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DOI：
10.1371/journal.pone.0071728
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Braun A
中科院分区：
文献类型：
--
作者：
Neuhaus V;Schwarz K;Klee A;Seehase S;Förster C;Pfennig O;Jonigk D;Fieguth HG;Koch W;Warnecke G;Yusibov V;Sewald K;Braun A
由新型流感病毒亚型引起的流感感染的年度爆发和人畜共患病的高发病率使季节性流感成为全球最不可预测和最严重的健康威胁之一。目前可用的疫苗虽然是主要的预防策略，但既不能有效地适应新的流行病毒亚型，也不能提供足够快的高数量以满足全球需求。需要能够迅速适应当前病毒株的新型流感疫苗。在本研究中，我们研究了一种新的吸入式流感疫苗在人精密切割肺切片（PCLS）病毒进入部位诱导抗原特异性回忆反应的局部毒性和能力。这种新疫苗结合了重组H1N1流感血凝素（HAC 1），在烟草植物中产生，和二氧化硅纳米颗粒（NP）为基础的药物输送系统。我们在适用浓度范围内未发现疫苗的局部细胞毒性。然而，较高浓度的NP（≥103 µg/ml）剂量依赖性地降低了人PCLS的活力。此外，NP而不是蛋白质引起TNF-α和IL-1β的剂量依赖性诱导，表明二氧化硅的佐剂性质。相比之下，我们发现与基线水平（152±49 pg/mg对22±5 pg/mg）相比，T细胞增殖和分化细胞因子IL-2的抗原特异性诱导，这在单独的NP中看不到。此外，与基线相比，用10 μg/ml HAC 1处理导致IFN-γ分泌增加6倍（602±307 pg/mg vs. 97±51 pg/mg）。这种抗原诱导的IFN-γ分泌通过二氧化硅NP对配制疫苗的佐剂作用进一步增强至12倍增加（97±51 pg/mg对比1226±535 pg/mg）。因此，我们能够表明，植物生产的疫苗诱导了足够的先天免疫应答，并在病毒进入部位的人PCLS中在无毒范围内重新激活了已建立的抗原特异性T细胞应答。
Annual outbreaks of influenza infections, caused by new influenza virus subtypes and high incidences of zoonosis, make seasonal influenza one of the most unpredictable and serious health threats worldwide. Currently available vaccines, though the main prevention strategy, can neither efficiently be adapted to new circulating virus subtypes nor provide high amounts to meet the global demand fast enough. New influenza vaccines quickly adapted to current virus strains are needed. In the present study we investigated the local toxicity and capacity of a new inhalable influenza vaccine to induce an antigen-specific recall response at the site of virus entry in human precision-cut lung slices (PCLS). This new vaccine combines recombinant H1N1 influenza hemagglutinin (HAC1), produced in tobacco plants, and a silica nanoparticle (NP)-based drug delivery system. We found no local cellular toxicity of the vaccine within applicable concentrations. However higher concentrations of NP (≥103 µg/ml) dose-dependently decreased viability of human PCLS. Furthermore NP, not the protein, provoked a dose-dependent induction of TNF-α and IL-1β, indicating adjuvant properties of silica. In contrast, we found an antigen-specific induction of the T cell proliferation and differentiation cytokine, IL-2, compared to baseline level (152±49 pg/mg vs. 22±5 pg/mg), which could not be seen for the NP alone. Additionally, treatment with 10 µg/ml HAC1 caused a 6-times higher secretion of IFN-γ compared to baseline (602±307 pg/mg vs. 97±51 pg/mg). This antigen-induced IFN-γ secretion was further boosted by the adjuvant effect of silica NP for the formulated vaccine to a 12-fold increase (97±51 pg/mg vs. 1226±535 pg/mg). Thus we were able to show that the plant-produced vaccine induced an adequate innate immune response and re-activated an established antigen-specific T cell response within a non-toxic range in human PCLS at the site of virus entry.
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