Euliano Erin M, Pogostin Brett H, Agrawal Anushka, Yu Marina H, Baryakova Tsvetelina H, Graf Tyler P, Hartgerink Jeffrey D, McHugh Kevin J
bioRxiv. 2024 Mar 9:2024.03.07.583938. doi: 10.1101/2024.03.07.583938.
UNLABELLED: Toll-like receptors (TLRs) recognize pathogen- and damage-associated molecular patterns and, in turn, trigger the release of cytokines and other immunostimulatory molecules. As a result, TLR agonists are increasingly being investigated as vaccine adjuvants, though many of these agonists are small molecules that quickly diffuse away from the vaccination site, limiting their co-localization with antigens and, thus, their effect. Here, the small-molecule TLR7 agonist 1V209 is conjugated to a positively-charged multidomain peptide (MDP) hydrogel, K , which was previously shown to act as an adjuvant promoting humoral immunity. Mixing the 1V209-conjugated K 50:50 with the unfunctionalized K produces hydrogels that retain the shear-thinning and self-healing physical properties of the original MDP, while improving the solubility of 1V209 more than 200-fold compared to the unconjugated molecule. When co-delivered with ovalbumin as a model antigen, 1V209-functionalized K produces antigen-specific IgG titers that were statistically similar to alum, the gold standard adjuvant, and a significantly lower ratio of Th2-associated IgG1 to Th1-associated IgG2a than alum, suggesting a more balanced Th1 and Th2 response. Together, these results suggest that K MDP hydrogels functionalized with 1V209 are a promising adjuvant for vaccines against infectious diseases, especially those benefiting from a combined Th1 and Th2 immune response. TABLE OF CONTENTS: Activation of toll-like receptors (TLRs) stimulates a signaling cascade to induce an immune response. A TLR7 agonist was conjugated to an injectable peptide hydrogel, which was then used to deliver a model vaccine antigen. This platform produced antibody titers similar to the gold standard adjuvant alum and demonstrated an improved balance between Th1- and Th2-mediated immunity over alum.
未标记:Toll样受体(TLRs)识别病原体和损伤相关分子模式,进而触发细胞因子和其他免疫刺激分子的释放。因此,TLR激动剂作为疫苗佐剂正受到越来越多的研究,尽管其中许多激动剂是小分子,会迅速从接种部位扩散,限制了它们与抗原的共定位,从而限制了它们的效果。在此,小分子TLR7激动剂1V209与带正电荷的多结构域肽(MDP)水凝胶K 偶联,K 先前已被证明可作为促进体液免疫的佐剂。将1V209偶联的K 与未功能化的K 以50:50混合,可产生保留原始MDP剪切变稀和自愈物理性质的水凝胶,同时与未偶联分子相比,将1V209的溶解度提高了200多倍。当与作为模型抗原的卵清蛋白共同递送时,1V209功能化的K 产生的抗原特异性IgG滴度在统计学上与金标准佐剂明矾相似,且与明矾相比,Th2相关的IgG1与Th1相关的IgG2a的比例显著更低,表明Th1和Th2反应更为平衡。总之,这些结果表明,用1V209功能化的K MDP水凝胶是一种有前途的针对传染病疫苗的佐剂,特别是那些受益于Th1和Th2联合免疫反应的疫苗。 目录:Toll样受体(TLRs)的激活刺激信号级联反应以诱导免疫反应。一种TLR7激动剂与可注射肽水凝胶偶联,然后用于递送模型疫苗抗原。该平台产生的抗体滴度与金标准佐剂明矾相似,并显示出与明矾相比,Th1和Th2介导的免疫之间的平衡得到改善。
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