Enhancing the efficacy of subunit vaccines relies significantly on the utilization of potent adjuvants, particularly those capable of triggering multiple immune pathways. To achieve synergistic immune augmentation by Toll-like receptor 4 agonist (TLR4a) and nucleotide-binding oligomerization-domain-containing protein 2 agonist (NOD2a), in this work, we conjugated RC529 (TLR4a) and MDP (NOD2a) to give RC529-MDP, and evaluated its adjuvanticity for OVA antigen. Compared to the unconjugated RC529+MDP, RC529-MDP remarkably enhanced innate immune responses with 6.8-fold increase in IL-6 cytokine, and promoted the maturation of antigen-presenting cells (APCs), possibly because of the conjugation of multiple agonists ensuring their delivery to the same cell and activation of various signaling pathways within that cell. Furthermore, RC529-MDP improved OVA-specific antibody response, T cells response and the memory T cells ratio relative to the unconjugated mixture. Therefore, covalently conjugating TLR4 agonist and NOD2 agonist was an effective strategy to enhance immune responses, providing the potential to design and develop more effective vaccines.

中文翻译：

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通过共价结合 TLR4 和 NOD2 激动剂实现协同免疫增强


增强亚单位疫苗的功效在很大程度上依赖于有效佐剂的使用，特别是那些能够触发多种免疫途径的佐剂。为了通过Toll样受体4激动剂（TLR4a）和含有核苷酸结合寡聚化结构域的蛋白2激动剂（NOD2a）实现协同免疫增强，在这项工作中，我们将RC529（TLR4a）和MDP（NOD2a）缀合以产生RC529- MDP，并评价其对OVA抗原的佐剂作用。与未缀合的 RC529+MDP 相比，RC529-MDP 显着增强了先天免疫反应，IL-6 细胞因子增加了 6.8 倍，并促进了抗原呈递细胞 (APC) 的成熟，这可能是因为多种激动剂的缀合确保了其递送至同一细胞并激活该细胞内的各种信号传导途径。此外，相对于未缀合的混合物，RC529-MDP 改善了 OVA 特异性抗体反应、T 细胞反应和记忆 T 细胞比率。因此，共价结合TLR4激动剂和NOD2激动剂是增强免疫反应的有效策略，为设计和开发更有效的疫苗提供了潜力。