Deal Cailin, Balazs Alejandro B, Espinosa Diego A, Zavala Fidel, Baltimore David, Ketner Gary
W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205;
Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139; and.
Proc Natl Acad Sci U S A. 2014 Aug 26;111(34):12528-32. doi: 10.1073/pnas.1407362111. Epub 2014 Aug 11.
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 µg/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.
每年,由恶性疟原虫引起的疟疾导致近100万儿童死亡,并给全球家庭和国家带来沉重的经济负担。目前尚无获批的疫苗,但可通过针对环子孢子蛋白(CSP)的抗体来预防感染,CSP是子孢子(即蚊子注入的寄生虫形式)的主要表面蛋白。我们利用基于腺相关病毒的载体免疫预防(VIP)技术,将编码抗恶性疟原虫CSP单克隆抗体的预制抗体基因导入小鼠体内。经VIP载体转导的小鼠血清中可长期表达单克隆抗体,浓度高达1200μg/mL,高达70%的小鼠在静脉注射和被转基因伯氏疟原虫啮齿类子孢子叮咬攻击后受到保护,这些子孢子在其CSP中含有该单克隆抗体的恶性疟原虫靶点。血清抗体水平和对蚊子叮咬攻击的保护作用取决于VIP载体的剂量。所有表达浓度为1mg/mL或更高的CSP特异性单克隆抗体2A10的小鼠均得到完全保护,这表明在该模型系统中,超过该阈值可实现持续的无菌保护。我们的结果证明了VIP作为实现难以捉摸的疟疾免疫目标的一条途径的潜力。
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