Delivering adjuvants and antigens in separate nanoparticles eliminates the need of physical linkage for effective vaccination
Delivering adjuvants and antigens in separate nanoparticles eliminates the need of physical linkage for effective vaccination
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DOI：
10.1016/j.jconrel.2017.02.031
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发表时间：
2017-04-10
影响因子：
10.8
通讯作者：
Bachmann, Martin F.
中科院分区：
文献类型：
--
作者：
Mohsen, Mona O.;Gomes, Ariane C.;Bachmann, Martin F.
富含未甲基化CG基序（CpG）的DNA接合内体中的Toll样受体9（TLR-9），并且是先天性和适应性免疫系统的充分描述的刺激物。因此，CpG可以有效地提高疫苗的免疫原性。将CpG包装到纳米颗粒中，特别是包装到病毒样颗粒（VLP）中，改善了CpG的药理学特征，因为蛋白质壳保护它们免受DNA酶活性的影响，并将寡聚体递送到专职抗原呈递细胞（APC）的内体区室。目前在基于VLP的疫苗中包装和递送CpG的共识是佐剂和抗原两者应保持紧密接近（即物理连接）以确保抗原和佐剂递送至相同的APC。在目前的研究中，我们利用淋巴系统的引流特性，并表明非连接的VLP也有效地共同递送到淋巴结中的相同APC。具体地，我们已经表明，CpG可以包装在一个VLP中，并在体内施用之前与展示抗原的另一个VLP混合。两种VLP有效地到达相同的引流淋巴结，在那里它们被相同的APC（即树突状细胞和巨噬细胞）吸收和加工。这导致在使用含有CpG和化学缀合的抗原的VLP时所见的水平下诱导产生细胞因子的特异性CTL并在体内杀死靶细胞。因此，在单独的纳米颗粒中递送抗原和佐剂消除了物理缀合的需要，并且因此在设计基于精确医学VLP的疫苗时可能是有益的，或者有助于重新配制现有的不天然携带免疫刺激序列的VLP疫苗。(C)2017爱思唯尔B. V.保留所有权利。
DNA rich in unmethylated CGmotifs (CpGs) engage Toll-Like Receptor 9 (TLR-9) in endosomes and are well described stimulators of the innate and adaptive immune system. CpGs therefore can efficiently improve vaccines' immunogenicity. Packaging CpGs into nanoparticles, in particular into virus-like particles (VLPs), improves the pharmacological characteristics of CpGs as the protein shell protects them from DNAse activity and delivers the oligomers to the endosomal compartments of professional antigen presenting cells (APCs). The current consensus in packaging and delivering CpGs in VLP-based vaccines is that both adjuvants and antigens should be kept in close proximity (i.e. physically linked) to ensure delivery of antigens and adjuvants to the same APCs. In the current study, we harness the draining properties of the lymphatic system and show that also non-linked VLPs are efficiently co-delivered to the same APCs in lymph nodes. Specifically, we have shown that CpGs can be packaged in one VLP and mixed with another VLP displaying the antigen prior to administration in vivo. Both VLPs efficiently reached the same draining lymph node where they were taken up and processed by the same APCs, namely dendritic cells and macrophages. This resulted in induction of specific CTLs producing cytokines and killing target cells in vivo at levels seen when using VLPs containing both CpGs and chemically conjugated antigen. Thus, delivery of antigens and adjuvants in separate nanoparticles eliminates the need of physical conjugation and thus can be beneficial when designing precision medicine VLP-based vaccines or help to re-formulate existing VLP vaccines not naturally carrying immunostimulatory sequences. (C) 2017 Elsevier B.V. All rights reserved.