Incorporation of a Toll-like receptor 2/6 agonist potentiates mRNA vaccines against cancer and infectious diseases.
Incorporation of a Toll-like receptor 2/6 agonist potentiates mRNA vaccines against cancer and infectious diseases.
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DOI：
10.1038/s41392-023-01479-4
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发表时间：
2023-07-17
影响因子：
39.3
通讯作者：
Shi, Huashan
中科院分区：
文献类型：
--
作者：
Gu, Yangzhuo;Yang, Jingyun;He, Cai;Zhao, Tingmei;Lu, Ran;Liu, Jian;Mo, Xianming;Wen, Fuqiang;Shi, Huashan
近年来，mRNA疫苗作为预防和治疗多种疾病（包括癌症和传染病）的药物迅速兴起。 mRNA疫苗的改进一直在进行中，其中提高功效非常重要。 Pam2Cys 是一种简单的合成可代谢脂氨基酸，通过 Toll 样受体 (TLR) 2/6 途径发出信号，引发体液和细胞适应性免疫反应，是一种有趣的候选佐剂。为了研究 Pam2Cys 对 mRNA 疫苗功效的增强，将佐剂掺入 mRNA-脂质纳米颗粒 (LNP) 中，实现与 mRNA 的共同递送。使用产生的 mRNA-LNP (Pam2Cys) 进行免疫，通过诱导 IL-12 和 IL-17 等细胞因子，塑造引流淋巴结 (dLN) 中的免疫环境。抗原呈递主要由迁移和 dLN 驻留的常规 2 型 DC (cDC2) 进行，并且在预防性和治疗性肿瘤模型中以 CD4+ 和 CD8+ T 细胞依赖性方式触发显着更有效的抗肿瘤反应。还建立了伴随记忆的抗肿瘤免疫。此外，该疫苗还在替代性 COVID-19 预防模型中刺激了更强大的体液和细胞免疫。最后但并非最不重要的一点是，新疫苗在小鼠模型中表现出良好的初步安全性。这些事实保证了未来开发掺有 Pam2Cys 的 mRNA 疫苗或相关 mRNA 疗法的临床应用。
mRNA vaccines have emerged rapidly in recent years as a prophylactic and therapeutic agent against various diseases including cancer and infectious diseases. Improvements of mRNA vaccines have been underway, among which boosting of efficacy is of great importance. Pam2Cys, a simple synthetic metabolizable lipoamino acid that signals through Toll-like receptor (TLR) 2/6 pathway, eliciting both humoral and cellular adaptive immune responses, is an interesting candidate adjuvant. To investigate the enhancement of the efficacies of mRNA vaccines by Pam2Cys, the adjuvant was incorporated into mRNA-lipid nanoparticles (LNPs) to achieve co-delivery with mRNA. Immunization with the resulting mRNA-LNPs (Pam2Cys) shaped up the immune milieu in the draining lymph nodes (dLNs) through the induction of IL-12 and IL-17, among other cytokines. Antigen presentation was carried out mainly by migratory and dLN-resident conventional type 2 DCs (cDC2s) and significantly more potent antitumor responses were triggered in both prophylactic and therapeutic tumor models in a CD4+ and CD8+ T cell-dependent fashion. Accompanying memory antitumor immunity was also established. Moreover, the vaccine also stimulated much more robust humoral and cellular immunity in a surrogate COVID-19 prophylactic model. Last but not the least, the new vaccines exhibited good preliminary safety profiles in murine models. These facts warrant future development of Pam2Cys-incorporated mRNA vaccines or relevant mRNA therapeutics for clinical application.
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影响因子：
9.9
作者：
Gu, Yangzhuo;Duan, Jiangyao;Yang, Na;Yang, Yuxin;Zhao, Xing
通讯作者：
Zhao, Xing
影响因子：
3.2
作者：
Halliday A;Turner JD;Guimarães A;Bates PA;Taylor MJ
通讯作者：
Taylor MJ
影响因子：
14
作者：
Islam MA;Rice J;Reesor E;Zope H;Tao W;Lim M;Ding J;Chen Y;Aduluso D;Zetter BR;Farokhzad OC;Shi J
通讯作者：
Shi J
DOI：
10.1073/pnas.0406740101
发表时间：
2004-10-26
影响因子：
11.1
作者：
Jackson, DC;Lau, YF;Brown, LE
通讯作者：
Brown, LE
影响因子：
5.4
作者：
Gopal, Radha;Lin, Yinyao;Obermajer, Natasa;Slight, Samantha;Nuthalapati, Nikhil;Ahmed, Mushtaq;Kalinski, Pawel;Khader, Shabaana A.
通讯作者：
Khader, Shabaana A.