In vivo characterization of the physicochemical properties of polymer-linked TLR agonists that enhance vaccine immunogenicity.
In vivo characterization of the physicochemical properties of polymer-linked TLR agonists that enhance vaccine immunogenicity.
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DOI：
10.1038/nbt.3371
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发表时间：
2015-11
影响因子：
46.9
通讯作者：
Seder RA
中科院分区：
文献类型：
--
作者：
Lynn GM;Laga R;Darrah PA;Ishizuka AS;Balaci AJ;Dulcey AE;Pechar M;Pola R;Gerner MY;Yamamoto A;Buechler CR;Quinn KM;Smelkinson MG;Vanek O;Cawood R;Hills T;Vasalatiy O;Kastenmüller K;Francica JR;Stutts L;Tom JK;Ryu KA;Esser-Kahn AP;Etrych T;Fisher KD;Seymour LW;Seder RA
疫苗佐剂如Toll样受体激动剂（TLRa）的功效可以通过配制和递送方法来改善。在这里，我们将小分子TLR-7/8a连接到聚合物支架（聚合物-TLR-7/8a）上，并评估TLR-7/8a和聚合物载体的不同理化性质如何影响体内先天免疫激活的位置、幅度和持续时间。聚合物-TLR-7/8a的颗粒形成对于限制佐剂分布和延长引流淋巴结中的活性至关重要。颗粒聚合物-TLR-7/8a改善的药代动力学特征也与发病率降低和诱导抗体和T细胞免疫的疫苗免疫原性增强相关。我们将这些发现扩展到模块化平台的开发，其中蛋白质抗原与温度响应性聚合物-TLR-7/8a佐剂位点特异性连接，所述温度响应性聚合物-TLR-7/8a佐剂在体内生理温度下自组装成免疫原性颗粒。我们的研究结果提供了一个化学和结构的基础，优化佐剂设计，引发广泛的抗体和T细胞反应的蛋白抗原。
The efficacy of vaccine adjuvants such as Toll-like receptor agonists (TLRa) can be improved through formulation and delivery approaches. Here, we attached small molecule TLR-7/8a to polymer scaffolds (polymer-TLR-7/8a) and evaluated how varying physicochemical properties of the TLR-7/8a and polymer carrier influenced the location, magnitude and duration of innate immune activation in vivo. Particle formation by polymer-TLR-7/8a was critical for restricting adjuvant distribution and prolonging activity in draining lymph nodes. The improved pharmacokinetic profile by particulate polymer-TLR-7/8a was also associated with reduced morbidity and enhanced vaccine immunogenicity for inducing antibodies and T cell immunity. We extended these findings to the development of a modular platform in which protein antigens are site-specifically linked to temperature-responsive polymer-TLR-7/8a adjuvants that self-assemble into immunogenic particles at physiologic temperatures in vivo. Our findings provide a chemical and structural basis for optimizing adjuvant design to elicit broad-based antibody and T cell responses with protein antigens.
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影响因子：
15.9
作者：
Kastenmueller, Kathrin;Wille-Reece, Ulrike;Seder, Robert A.
通讯作者：
Seder, Robert A.
影响因子：
7.3
作者：
Gerster, JF;Lindstrom, KJ;Lupu, M
通讯作者：
Lupu, M
DOI：
10.1073/pnas.1112648109
发表时间：
2012-01-24
影响因子：
11.1
作者：
Moon, James J.;Suh, Heikyung;Irvine, Darrell J.
通讯作者：
Irvine, Darrell J.
影响因子：
5.5
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
通讯作者：
Kishimoto, Takashi Kei
DOI：
10.1073/pnas.1105200108
发表时间：
2011-09-20
影响因子：
11.1
作者：
Jewell, Christopher M.;Lopez, Sandra C. Bustamante;Irvine, Darrell J.
通讯作者：
Irvine, Darrell J.