登革熱是全球重要的蟲媒病毒傳染病之一，每年造成數百萬的病例。主要是經由登革病毒 (dengue virus) 所引起，它屬於黃熱病毒科的正股單鏈RNA病毒，會造成的病症可從無症狀、較輕微的登革熱到嚴重危及生命的登革出血熱以及登革休克症候群。儘管目前已有數個國家在使用減毒登革疫苗Dengvaxia，但此疫苗對於登革病毒整體的效能依然存在風險。我們實驗室先前研究顯示，登革病毒的非結構性蛋白1 (NS1) 中的C端區域會誘發導致內皮細胞受損和血小板功能障礙的交叉反應性自身抗體。因此，我們將此區域利用日本腦炎病毒 (JEV) 的相同區域進行代替並產生名為DJ NS1的嵌合蛋白。先前研究指出，給予高分子奈米包裹DJ NS1蛋白複合物相較於DJ NS1蛋白添加鋁鹽的組別，更能誘導小鼠產生較高以及較久的抗體反應，並且在小鼠經登革病毒所導致的出血時間延長症狀中提供更好的保護。除了體液免疫反應，我們發現包裹在高分子奈米複合物中的DJ NS1抗原能較有效地被樹突狀細胞（dendritic cells）攝取以及使得樹突狀細胞能較持久的活化，進而誘導對於DJ NS1抗原有反應的CD4+ 和CD8+ T細胞的活化。此外，疫苗所提供的長期保護需要持續存在的抗體以及產生免疫記憶細胞。為了評估疫苗的有效性，我們證實給予包裹DJ NS1高分子奈米複合物的小鼠增加了中央記憶T細胞和效應記憶T細胞的產生，並且從給予包裹DJ NS1高分子奈米複合物免疫的小鼠中分離出的淋巴細胞，可藉由細胞介導的細胞毒殺功能將不同血清型登革病毒感染的細胞殺死。另外，我們的實驗結果顯示，在給予高分子奈米包裹DJ NS1蛋白複合物的CD4+ T細胞在登革病毒感染所引起的出血時間延長症狀的小鼠中提供保護作用。綜合以上結果顯示，使用包裹DJ NS1高分子奈米複合物能夠誘導持久的體液和細胞免疫反應，並提供對登革病毒感染的保護作用。這些結果表明包裹DJ NS1高分子奈米複合物是具有潛力的登革疫苗候選者。

Dengue is one of the most important worldwide arboviral infections and causes millions of cases annually. It is mainly caused by dengue virus (DENV) that is a positive single-stranded RNA virus of the Flaviviridae family and results in a range of diseases from asymptomatic, mild dengue fever to life-threatening dengue hemorrhagic fever and dengue shock syndrome. Although the live attenuated dengue vaccine Dengvaxia is available in several countries now, the risk of the overall efficacy remains concerned. Our previous studies showed that the C-terminal region of DENV NS1 can produce cross-reactive autoantibodies leading to endothelial cell damage and platelet dysfunction. Therefore, we replaced with the similar region of JEV NS1 to generate a chimeric DJ NS1 protein. The previous studies in our laboratory demonstrated that active immunization with DJ NS1 protein plus polymer-based nanocomplexes as adjuvant induces higher and longer antibody response as well as provides better protection in DENV-induced prolonged bleeding time than DJ NS1 protein plus Alum in mice. Besides the humoral immune responses, in this study we found that DJ NS1-encapsulated nanocomplexes (DJ NS1-NCs) were efficiently taken up into dendritic cells (DCs) and induced long-lasting activation of DCs, further induced both CD4+ and CD8+ T cell activation in response to DJ NS1 antigen. An ideal vaccine to provide long-term protection requires the persistence of antibodies and the generation of immune memory cells. To evaluate the vaccine efficacy, we demonstrated that DJ NS1-NCs increased the generation of both central memory T and effector memory T cells. Moreover, lymphocytes from mice immunized with DJ NS1-NCs had capability to kill different serotypes of DENV-infected cells through cell-mediated cytotoxicity. Furthermore, our studies showed that CD4+ T cells play a protective role in DENV-induced prolonged bleeding time. Taken together, DJ NS1-NCs induce the long-lasting humoral as well as cellular immune responses and provide protective efficacy against DENV. These results indicate that DJ NS1-NCs may have great potential as dengue vaccine candidate.

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