Vectored antibody gene delivery protects against Plasmodium falciparum sporozoite challenge in mice
Vectored antibody gene delivery protects against Plasmodium falciparum sporozoite challenge in mice
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DOI：
10.1073/pnas.1407362111
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发表时间：
2014-08-26
影响因子：
11.1
通讯作者：
Ketner, Gary
中科院分区：
文献类型：
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作者：
Deal, Cailin;Balazs, Alejandro B.;Ketner, Gary
由恶性疟原虫引起的疟疾每年造成近100万儿童死亡，并给全世界的家庭和国家带来沉重的经济负担。目前还没有获得许可的疫苗，但可以通过针对环子孢子蛋白（CSP）的抗体来预防感染，环子孢子蛋白是子孢子的主要表面蛋白，是蚊子注射的寄生虫的形式。我们已经使用载体免疫预防（VIP），一种基于腺相关病毒的技术，将编码抗恶性疟原虫CSP mAb的预制抗体基因导入小鼠。VIP载体转导的小鼠在血清中表现出高达1，200 μ g/mL的长寿命mAb表达，并且高达70%的小鼠被保护免受转基因伯氏疟原虫啮齿动物子孢子的静脉内和蚊子叮咬攻击，所述子孢子在其CSP中掺入mAb的恶性疟原虫靶标。血清抗体水平和对蚊子叮咬攻击的保护依赖于VIP载体的剂量。表达1 mg/mL或更高浓度的CSP特异性mAb 2A 10的所有个体小鼠均得到完全保护，表明在该模型系统中，超过该阈值导致一致的无菌保护。我们的研究结果表明，VIP作为实现疟疾免疫这一难以捉摸的目标的途径的潜力。
Malaria caused by Plasmodium falciparum kills nearly one million children each year and imposes crippling economic burdens on families and nations worldwide. No licensed vaccine exists, but infection can be prevented by antibodies against the circumsporozoite protein (CSP), the major surface protein of sporozoites, the form of the parasite injected by mosquitoes. We have used vectored immunoprophylaxis (VIP), an adeno-associated virus-based technology, to introduce preformed antibody genes encoding anti-P. falciparum CSP mAb into mice. VIP vector-transduced mice exhibited long-lived mAb expression at up to 1,200 mu g/mL in serum, and up to 70% were protected from both i.v. and mosquito bite challenge with transgenic Plasmodium berghei rodent sporozoites that incorporate the P. falciparum target of the mAb in their CSP. Serum antibody levels and protection from mosquito bite challenge were dependent on the dose of the VIP vector. All individual mice expressing CSP-specific mAb 2A10 at 1 mg/mL or more were completely protected, suggesting that in this model system, exceeding that threshold results in consistent sterile protection. Our results demonstrate the potential of VIP as a path toward the elusive goal of immunization against malaria.