Potency, efficacy and durability of DNA/DNA, DNA/protein and protein/protein based vaccination using gp63 against Leishmania donovani in BALB/c mice.
Potency, efficacy and durability of DNA/DNA, DNA/protein and protein/protein based vaccination using gp63 against Leishmania donovani in BALB/c mice.
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DOI：
10.1371/journal.pone.0014644
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发表时间：
2011-02-02
期刊：
影响因子：
3.7
通讯作者：
Ali N
中科院分区：
文献类型：
--
作者：
Mazumder S;Maji M;Das A;Ali N
由细胞内原生动物寄生虫利什曼原虫引起的内脏利什曼病（VL）在不治疗的情况下是致命的。目前还没有针对任何形式的利什曼病的有效疫苗。在这里，我们在易感小鼠模型中评估了针对 VL 的 DNA/DNA、DNA 初免/蛋白质加强和蛋白质/蛋白质疫苗接种的效力、功效和持久性。为了比较针对杜氏利什曼原虫的 DNA、蛋白质和异源初免加强 (HPB) 疫苗接种的效力、功效和持久性，将主要表面糖蛋白 gp63 克隆到哺乳动物表达载体 pcDNA3.1 中，用于基于 DNA 的疫苗。我们证明基于 gp63 DNA 的疫苗接种可诱导免疫反应并提供针对攻击感染的保护。然而，与其他方案相比，HPB 疫苗接种显示出相对增强的细胞和体液反应，并在感染前引发早期混合 Th1/Th2 反应。此外，与其他疫苗接种策略相比，寄生虫攻击诱导了极化的 Th1 反应，IFN-γ、IL-12、一氧化氮、IgG2a/IgG1 比率增强，IL-4 和 IL-10 反应降低。尽管在短期保护研究中，单独使用gp63 DNA或与CpG-ODN混合接种gp63 DNA或与CpG-ODN混合进行异源引发-加强显示出相当水平的保护作用，但在长期研究中，在CpG存在下的DNA引发/蛋白质加强显着降低了肝脏和脾脏寄生虫负荷，分别降低了107倍和1010倍。本研究中获得的保护程度迄今为止尚未在针对 VL 的易感 BALB/c 模型中通过 HPB 方法实现长期保护。有趣的是，HPB 方案还显示 BALB/c 小鼠针对利什曼原虫重大感染的足垫肿胀明显减少。基于 gp63 与 CpG 结合的 HPB 方法产生了强大的细胞和体液反应，与针对杜氏乳杆菌攻击的持久保护相关，直至疫苗接种后 12 周。这些结果强调了 DNA 初免/蛋白质加强疫苗接种相对于 DNA/DNA 和蛋白质/蛋白质疫苗接种在维持针对利什曼原虫等细胞内病原体的长期免疫力方面的潜力。
Visceral leishmaniasis (VL) caused by an intracellular protozoan parasite Leishmania, is fatal in the absence of treatment. At present there are no effective vaccines against any form of leishmaniasis. Here, we evaluate the potency, efficacy and durability of DNA/DNA, DNA-prime/Protein-boost, and Protein/Protein based vaccination against VL in a susceptible murine model. To compare the potency, efficacy, and durability of DNA, protein and heterologous prime-boost (HPB) vaccination against Leishmania donovani, major surface glycoprotein gp63 was cloned into mammalian expression vector pcDNA3.1 for DNA based vaccines. We demonstrated that gp63 DNA based vaccination induced immune responses and conferred protection against challenge infection. However, vaccination with HPB approach showed comparatively enhanced cellular and humoral responses than other regimens and elicited early mixed Th1/Th2 responses before infection. Moreover, challenge with parasites induced polarized Th1 responses with enhanced IFN-γ, IL-12, nitric oxide, IgG2a/IgG1 ratio and reduced IL-4 and IL-10 responses compared to other vaccination strategies. Although, vaccination with gp63 DNA either alone or mixed with CpG- ODN or heterologously prime-boosting with CpG- ODN showed comparable levels of protection at short-term protection study, DNA-prime/Protein-boost in presence of CpG significantly reduced hepatic and splenic parasite load by 107 fold and 1010 fold respectively, in long-term study. The extent of protection, obtained in this study has till now not been achieved in long-term protection through HPB approach in susceptible BALB/c model against VL. Interestingly, the HPB regimen also showed marked reduction in the footpad swelling of BALB/c mice against Leishmania major infection. HPB approach based on gp63 in association with CpG, resulted in robust cellular and humoral responses correlating with durable protection against L. donovani challenge till twelve weeks post-vaccination. These results emphasize the potential of DNA-prime/Protein-boost vaccination over DNA/DNA and Protein/Protein based vaccination in maintaining long-term immunity against intracellular pathogen like Leishmania.
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影响因子：
5.5
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