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Synergistic effect of dual targeting vaccine adjuvant with aminated β-glucan and CpG-oligodeoxynucleotides for both humoral and cellular immune responses
Acta Biomaterialia ( IF 9.7 ) Pub Date : 2018-08-09 , DOI: 10.1016/j.actbio.2018.08.002
Jing Wei Jin , Shun Qing Tang , Min Zhi Rong , Ming Qiu Zhang

Presently, clinically approved adjuvants (such as aluminum salts) fail to induce cellular immune responses, which is crucial to defend against intracellular pathogens (including HIV, malaria, tuberculosis and Ebola) and cancer. However, Freund’s complete adjuvant potently stimulates both humoral and cellular immune responses, accompanying by high toxicity and severe side reactions. Here in this work, a CpG-oligodeoxynucleotides (CpG-OND) crosslinked aminated β-glucan-Ovalbumin dual targeting nanoparticle (CpG-OND-AG-OVA) is prepared through a simple and mild ionic complexation method. The aminated β-glucan plays dual roles as antigen presenting cells (APCs) targeted carrier and immunopotentiator (targeting and activating dectin-1 on APCs). Meanwhile, CpG-OND also plays dual roles as ionic crosslinker and immunopotentiator (targeting and activating Toll-like receptor 9 in APCs). The adjuvant activity of the particles is evaluated through in vitro and in vivo experiments. The particles significantly enhance uptake and sustained proteolytic processing of antigens, and result in APCs maturation, inducing robust Th1 and Th2-type immune responses comparable to Freund’s adjuvant without obvious toxicity. The potent adjuvant activity of the nanoparticles may originate from dual targeting synergistic effects between aminated β-glucan and CpG-OND. Accordingly, the dual targeting nanoparticles may be a promising vaccine adjuvant for inducing robust humoral and cellular immune responses against infectious diseases and cancers.

Statement of Significance

An ideal adjuvant for subunit vaccine should act as both a carrier to enhance the uptake, sustained processing and cytosolic delivery of antigens, and an immunopotentiator to stimulate antigen presenting cells (APCs) for activation of naive T cells. Additionally, it should be easy to obtain and safe with negligible toxicity. Unfortunately, both synthetic and natural polymers that have been developed into antigen delivery system cannot completely fulfill the requirements. In the present study, the authors design nanoparticles with aminated β-glucan and CpG-oligodeoxynucleotides (CpG-OND) through a simple and mild method. β-Glucan (a dectin-1 and TLR2 targeted PAMP) and CpG-OND (a TLR9 targeted PAMP) are readily accessible. Aminated β-glucan plays dual roles in the nanoparticle as APCs targeted carrier and immunopotentiator. Meanwhile, CpG-OND also plays dual roles as crosslinker and APCs targeted immunopotentiator. By making use of synergistic effect of the dual targeting vaccine adjuvant with aminated β-glucan and CpG-OND, the nanoparticles induce robust antigen specific immune responses comparable to Freund’s adjuvant without obvious toxicity.



中文翻译:

双靶向疫苗佐剂与胺化β-葡聚糖和CpG-寡脱氧核苷酸的协同作用对体液和细胞免疫反应的协同作用

目前,临床上认可的佐剂(如铝盐)无法诱导细胞免疫反应,这对于防御细胞内病原体(包括HIV,疟疾,结核病和埃博拉病毒)和癌症至关重要。但是,弗氏完全佐剂可有效刺激体液和细胞免疫反应,并伴有高毒性和严重的副反应。在这项工作中,这是一个CpG-寡脱氧核苷酸CpG-OND)交联的胺化β-葡聚糖-卵清蛋白双重靶向纳米颗粒(CpG-OND-AG-OVA)是通过一种简单温和的离子络合方法制备的。胺化的β-葡聚糖起着抗原呈递细胞(APC)靶向载体和免疫增强剂(在APC上靶向和激活dectin-1)的双重作用。同时,CpG-OND还起着离子交联剂和免疫增强剂(在APC中靶向并激活Toll样受体9)的双重作用。通过体外和体内实验评估颗粒的佐剂活性。该颗粒显着增强了抗原的摄取和持续的蛋白水解过程,并导致APC成熟,诱导了与弗氏佐剂相当的强大的Th1和Th2型免疫反应,而没有明显的毒性。纳米颗粒的有效佐剂活性可以源自胺化的β-葡聚糖和CpG-OND之间的双重靶向协同作用。因此,双重靶向纳米颗粒可能是用于诱导针对感染性疾病和癌症的强健的体液和细胞免疫应答的有前途的疫苗佐剂。

重要声明

亚单位疫苗的理想佐剂既可以充当增强抗原摄取,持续加工和胞质递送的载体,又可以充当刺激抗原呈递细胞(APC)激活幼稚T细胞的免疫增强剂。此外,它应该易于获得并且毒性可忽略不计。不幸的是,已经发展成抗原递送系统的合成和天然聚合物都不能完全满足要求。在本研究中,作者通过一种简单温和的方法设计了具有胺化β-葡聚糖和CpG-寡脱氧核苷酸(CpG-OND)的纳米颗粒。容易获得β-葡聚糖(dectin-1和TLR2靶向PAMP)和CpG-OND(TLR9靶向PAMP)。胺化的β-葡聚糖在纳米颗粒中起着双重作用,作为APCs靶向的载体和免疫增强剂。同时,CpG-OND还起着交联剂和APC靶向免疫增强剂的双重作用。通过利用双重靶向疫苗佐剂与胺化的β-葡聚糖和CpG-OND的协同作用,纳米颗粒可诱导产生与弗氏佐剂相当的强大的抗原特异性免疫反应,而没有明显的毒性。

更新日期:2018-08-10
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