Thermophobic Trehalose Glycopolymers as Smart C-Type Lectin Receptor Vaccine Adjuvants.
Thermophobic Trehalose Glycopolymers as Smart C-Type Lectin Receptor Vaccine Adjuvants.
复制标题
疏热海藻糖糖聚合物作为智能 C 型凝集素受体疫苗佐剂。
DOI：
10.1002/adhm.202202918
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发表时间：
2023
影响因子：
10
通讯作者：
Mancini,RockJ
中科院分区：
文献类型：
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作者：
Hendricksen,AaronT;Ezzatpour,Shahrzad;Pulukuri,AnunayJ;Ryan,AustinT;Flanagan,TatumJ;Frantz,William;Buchholz,DavidW;Ortega,Victoria;Monreal,IsaacA;Sahler,JulieM;Nielsen,AmyE;Aguilar,HectorC;Mancini,RockJ
在此，这项工作报告了第一种合成疫苗佐剂，其响应于其较低临界溶液温度（LCST）附近的温度的小的1-2 °C变化而减弱效力。佐剂添加剂显著提高疫苗效力。然而，佐剂也会引起炎症副作用，如发热，这目前限制了它们的使用。为了解决这个问题，产生了一种工程化的疏热疫苗佐剂，以减弱在与发热相关的温度下的效力。通过可逆加成断裂链转移（RAFT）聚合将合理设计的海藻糖糖脂疫苗佐剂与温敏性聚N-异丙基丙烯酰胺（NIPAM）组合来合成疏热佐剂。所得的疏热佐剂在37 °C附近表现出LCST，并自组装成具有温度依赖性尺寸（90-270 nm）的纳米颗粒。疏热佐剂激活HEK-mMINCLE和其他先天性免疫细胞系以及原代小鼠骨髓来源的树突状细胞（BMDC）和骨髓来源的巨噬细胞（BMDM）。相对于稳态（37 °C）或低于LCST，在模拟发热（高于LCST）的条件下，炎性细胞因子的产生减弱。这种疏热行为与通过DLS观察到的降低的疏水性Rgis以及通过NOESY-NMR观察到的糖脂-NIPAM屏蔽相互作用相关。在体内，与未加佐剂的对照疫苗相比，通过增加中和抗体滴度和CD 4 +/44+/62 L+肺和淋巴结中央记忆T细胞，以及在病毒攻击后提供更好的免于发病的保护，疏热佐剂增强了完整灭活流感A/加州/04/2009病毒疫苗的功效。总之，这些结果证明了具有由温度调节的效力的第一佐剂。这项工作设想，随着进一步的研究，这种方法可以提高疫苗的有效性，同时保持安全性。
Herein, this work reports the first synthetic vaccine adjuvants that attenuate potency in response to small, 1–2 °C changes in temperature about their lower critical solution temperature (LCST). Adjuvant additives significantly increase vaccine efficacy. However, adjuvants also cause inflammatory side effects, such as pyrexia, which currently limits their use. To address this, a thermophobic vaccine adjuvant engineered to attenuate potency at temperatures correlating to pyrexia is created. Thermophobic adjuvants are synthesized by combining a rationally designed trehalose glycolipid vaccine adjuvant with thermoresponsive poly‐N‐isoporpylacrylamide (NIPAM) via reversible addition fragmentation chain transfer (RAFT) polymerization. The resulting thermophobic adjuvants exhibit LCSTs near 37 °C, and self‐assembled into nanoparticles with temperature‐dependent sizes (90–270 nm). Thermophobic adjuvants activate HEK‐mMINCLE and other innate immune cell lines as well as primary mouse bone marrow derived dendritic cells (BMDCs) and bone marrow derived macrophages (BMDMs). Inflammatory cytokine production is attenuated under conditions mimicking pyrexia (above the LCST) relative to homeostasis (37 °C) or below the LCST. This thermophobic behavior correlated with decreased adjuvantRgis observed by DLS, as well as glycolipid‐NIPAM shielding interactions are observed by NOESY‐NMR. In vivo, thermophobic adjuvants enhance efficacy of a whole inactivated influenza A/California/04/2009 virus vaccine, by increasing neutralizing antibody titers and CD4+/44+/62L+lung and lymph node central memory T cells, as well as providing better protection from morbidity after viral challenge relative to unadjuvanted control vaccine. Together, these results demonstrate the first adjuvants with potency regulated by temperature. This work envisions that with further investigation, this approach can enhance vaccine efficacy while maintaining safety.