Adjuvant-carrying synthetic vaccine particles augment the immune response to encapsulated antigen and exhibit strong local immune activation without inducing systemic cytokine release.
Adjuvant-carrying synthetic vaccine particles augment the immune response to encapsulated antigen and exhibit strong local immune activation without inducing systemic cytokine release.
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DOI：
10.1016/j.vaccine.2014.02.027
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发表时间：
2014-05-19
期刊：
影响因子：
5.5
通讯作者：
Kishimoto, Takashi Kei
中科院分区：
文献类型：
--
作者：
Ilyinskii, Petr O.;Roy, Christopher J.;O'Neil, Conlin P.;Browning, Erica A.;Pittet, Lynnelle A.;Altreuter, David H.;Alexis, Frank;Tonti, Elena;Shi, Jinjun;Basto, Pamela A.;Iannacone, Matteo;Radovic-Moreno, Aleksandar F.;Langer, Robert S.;Farokhzad, Omid C.;von Andrian, Ulrich H.;Johnston, Lloyd P. M.;Kishimoto, Takashi Kei
免疫原性的增强可以通过抗原的颗粒递送以及通过其与佐剂的共施用来实现。然而，许多佐剂在体内引发强烈的全身炎症反应，导致潜在的不良事件和安全性问题。我们开发了一种合成疫苗颗粒（SVP）技术，该技术能够将抗原与有效佐剂共包封。我们证明了在合成聚合物纳米颗粒中抗原与TLR 7/8或TLR 9激动剂的共递送导致体液和细胞免疫应答的强烈增强，同时全身产生的炎性细胞因子最少。相比之下，包封到纳米颗粒中并与游离TLR 7/8激动剂混合的抗原导致较低的免疫原性和血清中高水平炎性细胞因子的快速诱导（例如，注射游离瑞喹莫特（R848）后，TNF-α和IL-6水平比注射纳米颗粒包封的R848高50- 200倍。相反，当使用SVP包封的TLR激动剂时，由引流淋巴结的细胞浸润和结内细胞因子产生证明的局部免疫刺激更明显并且持续更长时间。使用模块化自组装纳米颗粒平台实现的强局部免疫激活显著增强免疫原性，并且无论抗原和佐剂是共同包封在单个纳米颗粒制剂中还是共同递送在两个单独的纳米颗粒中，都是同样有效的。此外，颗粒包封使得能够利用具有天然磷酸二酯骨架的CpG寡核苷酸，其否则在体内被核酸酶快速水解。SVP的使用可以使有效TLR激动剂作为疫苗佐剂用于需要细胞免疫或强体液应答的适应症的临床用途成为可能。
Augmentation of immunogenicity can be achieved by particulate delivery of an antigen and by its co-administration with an adjuvant. However, many adjuvants initiate strong systemic inflammatory reactions in vivo, leading to potential adverse events and safety concerns. We have developed a synthetic vaccine particle (SVP) technology that enables co-encapsulation of antigen with potent adjuvants. We demonstrate that co-delivery of an antigen with a TLR7/8 or TLR9 agonist in synthetic polymer nanoparticles results in a strong augmentation of humoral and cellular immune responses with minimal systemic production of inflammatory cytokines. In contrast, antigen encapsulated into nanoparticles and admixed with free TLR7/8 agonist leads to lower immunogenicity and rapid induction of high levels of inflammatory cytokines in the serum (e.g., TNF-α and IL-6 levels are 50- to 200-fold higher upon injection of free resiquimod (R848) than of nanoparticle-encapsulated R848). Conversely, local immune stimulation as evidenced by cellular infiltration of draining lymph nodes and by intranodal cytokine production was more pronounced and persisted longer when SVP-encapsulated TLR agonists were used. The strong local immune activation achieved using a modular self-assembling nanoparticle platform markedly enhanced immunogenicity and was equally effective whether antigen and adjuvant were co-encapsulated in a single nanoparticle formulation or co-delivered in two separate nanoparticles. Moreover, particle encapsulation enabled the utilization of CpG oligonucleotides with the natural phosphodiester backbone, which are otherwise rapidly hydrolyzed by nucleases in vivo. The use of SVP may enable clinical use of potent TLR agonists as vaccine adjuvants for indications where cellular immunity or robust humoral responses are required.
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影响因子：
15.9
作者：
Carpentier, A;Laigle-Donadey, F;Carpentier, AF
通讯作者：
Carpentier, AF
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0.2
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5.5
作者：
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通讯作者：
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