Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, International Joint Research Center for Intelligent Biosensing Technology and Health, Hubei International Scientific and Technological Cooperation Base of Pesticide and Green Synthesis, College of Chemistry, Central China Normal University, Wuhan 430079, China.
Jiangsu East-Mab Biomedical Technology Co. Ltd, Nantong 226499, China.
J Control Release. 2023 Mar;355:238-247. doi: 10.1016/j.jconrel.2023.01.062. Epub 2023 Feb 8.
Self-adjuvanting protein vaccines have been proved to be highly immunogenic with efficient codelivery of adjuvant and antigen. Current protein vaccines with built-in adjuvants are all modified at the peptide backbone of antigen protein, which could not achieve minor epitope interference and adjuvant multivalency at the same time. Herein, we developed a new conjugate strategy to construct effective adjuvant-protein vaccine with adjuvant cluster effect and minimal epitope interference. The toll-like receptor 7 agonist (TLR7a) is covalently conjugated on the terminal sialoglycans of SARS-CoV-2-S1 protein, leading to intracellular release of the small-molecule stimulators with greatly reduced risks of systemic toxicity. The resulting TLR7a-S1 conjugate elicited strong activation of immune cells in vitro, and potent antibody and cellular responses with a significantly enhanced Th1-bias in vivo. TLR7a-S1-induced antibody also effectively cross-neutralized all variants of concern. This sialoglycoconjugation approach to construct protein conjugate vaccines will have more applications to combat SARS-CoV-2 and other diseases.
自佐剂蛋白疫苗已被证明具有高度免疫原性，能够有效共递抗原和佐剂。目前具有内置佐剂的蛋白疫苗都是在抗原蛋白的肽主链上进行修饰的，这不能同时实现小表位干扰和佐剂多价性。在此，我们开发了一种新的偶联策略，构建具有佐剂簇效应和最小表位干扰的有效佐剂-蛋白疫苗。Toll 样受体 7 激动剂 (TLR7a) 共价连接在 SARS-CoV-2-S1 蛋白末端的唾液糖上，导致小分子刺激物在细胞内释放，大大降低了全身毒性的风险。由此产生的 TLR7a-S1 缀合物在体外强烈激活免疫细胞，并在体内产生强烈的抗体和细胞反应，显著增强了 Th1 偏向性。TLR7a-S1 诱导的抗体也能有效中和所有关注的变体。这种唾液糖缀合方法构建蛋白缀合物疫苗将有更多的应用来对抗 SARS-CoV-2 和其他疾病。
