登革病毒（DENV）是一種正股的單鏈RNA病毒，每年導致約3.9億個感染病例。迫切需要開發有效且安全的抗登革疫苗。先前研究中，由於非結構性蛋白1（NS1）的C端（271-352氨基酸）與血小板和內皮細胞呈現相似的表面抗原，可能會有交叉反應的疑慮而被修飾為ΔC NS1和DJ NS1。ΔC NS1和DJ NS1所誘導的抗體可以降低小鼠因登革病毒感染導致出血時間的延長。此外，一致性外膜蛋白第三結構域（cEDIII）在四型登革病毒中具有相似的氨基酸序列，所誘導的抗體對於四型登革病毒皆具有中和活性。因此，在先前的研究中將其合成為重組蛋白cEDIII-ΔC NS1並以此免疫小鼠，發現其血清不僅對四型登革病毒皆具有中和活性，並且能透過補體介導的毒殺功能殺死被四型登革病毒感染的HMEC-1細胞。我們進一步比較了cEDIII-ΔC NS1與cEDIII加上DJ NS1作為疫苗的可能性。考慮到cEDIII和DJ NS1之間的分子大小差異，我們測試了這兩種蛋白質的不同比例，發現給予每隻小鼠 5 μg 的cEDIII與 20 μg DJ NS1在誘導抗cEDIII和抗DJ NS1上有較佳的血清效價。在評估小鼠的抗體效價時，我們發現以cEDIII-ΔC NS1或cEDIII加上DJ NS1去免疫6-8週齡的小鼠，所誘導的抗cEDIII和抗DJ NS1抗體有相似的血清效價。在細胞試驗中，我們發現不論是cEDIII-ΔC NS1或是cEDIII加上DJ NS1誘導的抗體不僅對登革病毒有中和能力，且能與補體共同作用殺死被登革病毒感染的細胞。為了測試cEDIII-ΔC NS1在較小週齡小鼠的免疫效果，我們進一步評估了cEDIII-ΔC NS1對3週齡小鼠在登革病毒感染的保護作用。3週齡小鼠和6至8週齡小鼠經三劑免疫後誘導的抗cEDIII和抗NS1的血清效價沒有顯著差異。相較於僅以登革病毒或加上明礬感染的組別，cEDIII-ΔC NS1免疫的3週齡小鼠在登革病毒感染後顯示出較低的出血時間、血中病毒量以及NS1量。整體來說，研究結果顯示，cEDIII-ΔC NS1誘導的抗體不僅在細胞試驗中顯示出抗病毒功效，並在登革病毒感染小鼠模型中提供保護作用，是具有潛力的登革候選疫苗。

Dengue virus (DENV), which causes about 390 million infection cases per year, is a positive-sense, single-stranded RNA virus. The development of an effective and safe vaccine for DENV infection is in urgent need. In our previous studies, C-terminal region (271-352 amino acids) of nonstructural protein 1 (NS1) was modified into ΔC NS1 and DJ NS1, due to the existence of cross-reactive epitopes which mimic the surface antigens of platelets and endothelial cells. Antibodies against ΔC NS1 and DJ NS1 can reduce DENV-induced prolonged bleeding time in mice. Also, antibody against consensus envelope protein domain III (cEDIII), of which the amino acid sequences are consensus among four serotypes of DENV, showed neutralizing activity against all the four serotypes of DENV. In our previous studies, a recombinant protein cEDIII-ΔC NS1 was generated and the sera collected from cEDIII-ΔC NS1-immunized mice neutralized four serotypes of DENV and also caused complement-mediated cytolysis on HMEC-1 cells infected by four different serotypes of DENV. We further compared cEDIII-ΔC NS1 with cEDIII plus DJ NS1 for potential vaccine candidate. Considering the size difference between cEDIII and DJ NS1, we tested different ratios of these two proteins and found better serum titers of anti-cEDIII and anti-DJ NS1 using a combination of cEDIII (5 μg/mouse) with DJ NS1 (20 μg/mouse) for immunization. When exploring the antibody titers of cEDIII-ΔC NS1-immunized mice, we actually found similar serum titers of anti-cEDIII and anti-DJ NS1 as those immunized with cEDIII plus DJ NS1 in 6-8-week-old mice. In cellular test, we found that antibodies induced by cEDIII-ΔC NS1 or cEDIII combined with DJ NS1 showed not only neutralizing ability to DENV but also cytolytic ability to DENV-infected cells in the presence of complement. For the purpose of vaccine administration at early age, we further evaluated the protective effects of cEDIII-ΔC NS1 against DENV infection in 3-week-old mice. The serum titers against cEDIII and NS1 showed no significant difference after 3-time immunization between 3-week-old mice and 6-8-week-old mice. The cEDIII-ΔC NS1-immunized mice displayed lower bleeding time, viral titer, and plasma NS1 level in 3-week-old mice after DENV infection as compared with mice infected with DENV alone or DENV plus alum. Overall, the results in the study reveal that antibodies induced by cEDIII-ΔC NS1 not only show anti-viral efficacy in the cellular test but also provide protective effects in DENV infection mouse model, which provides a potential strategy for dengue vaccine candidates.

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