登革病毒（DENV）是一種正股的單鏈RNA病毒，每年感染約3.9億人。由於與宿主自身抗原的分子相似，登革病毒非結構蛋白1（NS1）的C-末端區域含有與血小板和內皮細胞交叉反應的抗原決定位。為了考量疫苗開發的安全性，我們修改了NS1蛋白的C-末端區域（271-352氨基酸），以產生兩種蛋白疫苗，即ΔC NS1和DJ NS1。以被動免疫方式將抗ΔC NS1和抗DJ NS1抗體注入小鼠體内可減少登革病毒引起的延長出血時間和登革病毒非結構蛋白三（NS3）抗原的表達。抗ΔC NS1和抗DJ NS1抗體均可通過抗體-補體介導的方式來破壞被登革病毒感染的細胞。另外，一致性外膜蛋白第三結構（cEDIII）所誘導出的抗體具有對四種血清型登革病毒中和的能力。為了開發能夠誘導具有中和活性和抗體-補體介導將細胞溶解功能的抗體的疫苗，我們經由融合cEDIII和ΔC NS1開發了重組蛋白。先前的研究顯示，cEDIII-ΔC NS1蛋白在小鼠中不會引起急性毒性或長期出血。接著我們利用奈米聚合物或明礬作為佐劑混合的cEDIII-ΔC NS1蛋白免疫小鼠。在第三次免疫後產生了對cEDIII和ΔC NS1的高抗體反應。通過溶斑減少試驗法測定，從cEDIII-ΔC NS1蛋白所免疫的小鼠收集的血清可中和四種血清型的登革病毒。此外，cEDIII-ΔC NS1血清對由四種不同血清型登革病毒感染的HMEC-1細胞產生補體介導的細胞溶解。cEDIII-ΔC NS1蛋白的預注射減少了因登革病毒引起小鼠尾巴延長出血時間。此外，cEDIII-ΔC NS1血清可防止被登革病毒感染的仔鼠之體重減輕、減少神經病理學症狀與提高存活率。總體來說，cEDIII-ΔC NS1蛋白是提供防禦登革病毒感染有潛力的候選疫苗。

Dengue virus (DENV) is a positive-sense, single-stranded RNA virus of which infects about 390 million people per year. Based on sequence homology analysis, the C-terminal region of DENV nonstructural protein 1 (NS1) contains cross-reactive epitopes with platelets and endothelial cells due to a molecular mimicry with host self-antigens. For safety in vaccine development, we modified the C-terminal region (271-352 amino acids) of NS1 protein to produce two types of vaccine candidates, ΔC NS1 and DJ NS1. Passive immunization with anti-ΔC NS1 and anti-DJ NS1 antibodies reduced DENV-induced prolonged bleeding time, hemorrhage, and DENV NS3 expression. Both anti-ΔC NS1 and anti-DJ NS1 antibodies destroy DENV-infected cells through antibody-complement mediated cytolysis. In addition, the antibodies against consensus envelope protein domain III (cEDIII), of which the amino acid sequences are consensus among four serotypes, possessed neutralizing activity against all the four serotypes of DENV. In order to develop a vaccine candidate that can induce antibodies with both neutralizing activity and antibody-complement mediated cytolysis function, we therefore developed a recombinant protein by fusing cEDIII and ΔC NS1. Previous study showed that the cEDIII-ΔC NS1 protein did not cause acute toxicity or prolonged bleeding in mice. Then, we immunized mice with cEDIII-ΔC NS1 protein mixed with polymer-based nanocomplexes or alum as adjuvant. A high antibody response specific to cEDIII and ΔC NS1 was produced after third immunization. The sera collected from cEDIII-ΔC NS1-immunized mice neutralized 4 serotypes of DENV as determined by plaque neutralization assay. Moreover, the cEDIII-ΔC NS1 serum caused complement-mediated cytolysis on HMEC-1 cells infected by four different serotypes of DENV. The pretreatment of cEDIII-ΔC NS1 protein reduced DENV-induced mouse-tail prolonged bleeding time. Furthermore, cEDIII-ΔC NS1 serum can prevent weight loss, reduce neuropathological symptoms and increase survival rate of DENV-infected suckling mice. Taken together, the cEDIII-ΔC NS1 protein is a potential candidate to provide protection against DENV infection.

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