In Vivo and In Vitro Potency of Polyphosphazene Immunoadjuvants with Hepatitis C Virus Antigen and the Role of Their Supramolecular Assembly.
In Vivo and In Vitro Potency of Polyphosphazene Immunoadjuvants with Hepatitis C Virus Antigen and the Role of Their Supramolecular Assembly.
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DOI：
10.1021/acs.molpharmaceut.0c00487
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发表时间：
2021-02-01
影响因子：
4.9
通讯作者：
Fuerst TR
中科院分区：
文献类型：
--
作者：
Andrianov AK;Marin A;Wang R;Chowdhury A;Agnihotri P;Yunus AS;Pierce BG;Mariuzza RA;Fuerst TR
研究了两种定义明确的合成聚磷腈免疫佐剂PCPP和PCEP在体内增强对丙型肝炎病毒（HCV）E2糖蛋白抗原的免疫应答的能力。我们报告说，PCEP诱导显着更高的血清中和和HCV特异性IgG滴度的小鼠相比，在研究中使用的其他佐剂：PCPP，明矾，和Addavax。PCEP还将应答向所需的平衡的Th 1/Th 2免疫转移，如通过抗体同种型比率（IgG 2a/IgG 1）所评价的。在系统中抗原-佐剂分子相互作用和制剂的体外免疫刺激活性的背景下分析体内结果。不对称流场流动分级分离（AF 4）和动态光散射（DLS）分析表明，PCPP和PCEP自发地与E2糖蛋白自组装，形成多聚体水溶性复合物，这表明聚磷腈大分子作为疫苗递送载体的作用。使用小鼠巨噬细胞系评估的聚磷腈佐剂的内在体外免疫刺激活性揭示了两种聚合物的可比活性，并且没有提供对其体内性能的解释。然而，与E2的PCEP复合物显示出更大的抗团聚稳定性和改善的体外免疫刺激活性相比，PCPP，这是符合上级在体内性能的PCEP。这些结果强调了制剂中经常被忽视的抗原-聚磷腈自组装机制的重要性，这可以为其体内行为提供重要的见解，并促进这类重要免疫佐剂的构效关系的建立。
Two well-defined synthetic polyphosphazene immunoadjuvants, PCPP and PCEP, were studied for their ability to potentiate immune response to Hepatitis C virus (HCV) E2 glycoprotein antigen in vivo. We report that PCEP induced significantly higher serum neutralization and HCV specific IgG titers in mice compared to other adjuvants used in the study: PCPP, Alum, and Addavax. PCEP also shifted the response toward desirable balanced Th1/Th2 immunity, as evaluated by antibody isotype ratio (IgG2a/IgG1). The in vivo results were analyzed in the context of antigen-adjuvant molecular interactions in the system and in vitro immunostimulatory activity of formulations. Asymmetric flow field flow fractionation (AF4) and dynamic light scattering (DLS) analysis showed that both PCPP and PCEP spontaneously self-assemble with the E2 glycoprotein with the formation of multimeric water-soluble complexes, which demonstrates the role of polyphosphazene macromolecules as vaccine delivery vehicles. Intrinsic in vitro immunostimulatory activity of polyphosphazene adjuvants, which was assessed using a mouse macrophage cell line, revealed comparable activities of both polymers and did not provide an explanation of their in vivo performance. However, PCEP complexes with E2 displayed greater stability against agglomeration and improved in vitro immunostimulatory activity compared to those of PCPP, which is in line with superior in vivo performance of PCEP. The results emphasize the importance of often neglected antigen-polyphosphazene self-assembly mechanisms in formulations, which can provide important insights on their in vivo behavior and facilitate the establishment of structure-activity relationship for this important class of immunoadjuvants.
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影响因子：
7.3
作者：
Grødeland G;Fossum E;Bogen B
通讯作者：
Bogen B
影响因子：
4
作者：
Andrianov AK;Marin A;Fuerst TR
通讯作者：
Fuerst TR
DOI：
10.1038/nri3694
发表时间：
2014-07
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
De Gregorio E;Rappuoli R
通讯作者：
Rappuoli R
影响因子：
7.6
作者：
Ison MG;Mills J;Openshaw P;Zambon M;Osterhaus A;Hayden F
通讯作者：
Hayden F
影响因子：
6.2
作者：
Andrianov, AK;Marin, A;Chen, JP
通讯作者：
Chen, JP