Vaccination with purified, cryopreserved, infectious Plasmodium vivax sporozoites

描述(由申请人提供)：间日疟原虫(PV)是第二大人类疟疾寄生虫，每年造成8000万例疟疾病例。然而，预防和控制光伏疟疾的努力面临着抗药性和休眠形式反复复发的重大挑战。此外，由于光伏寄生虫不能在连续的体外培养中生长，光伏疫苗的开发受到了阻碍。在制造了世界上唯一的纯化、冷冻保存的间日疟原虫(PV)子孢子(SPZ)，并表明这些冷冻保存的PvSPZ可以用于感染黑猩猩和体外感染肝细胞后，Sanaria现在准备将这些传染性的PvSPZ用作针对PV的第一个完整寄生虫疫苗。该战略利用了仅有的两种方法中的一种的成功，这两种方法曾在人类中诱导对肺吸虫病的长期免疫，一种使用辐射衰减的方法，另一种使用含有氯喹的非减毒完全传染性SPZ。在一篇开创性的论文中显示，在服用氯喹的志愿者中，携带完全传染性恶性疟原虫子孢子(PfSPZ)的蚊子叮咬免疫可诱导100%的保护性免疫，在末次免疫后28个月仍有保护作用。Sanaria独特的技术平台使这一观察结果能够立即转化为制造冷冻保存的传染性PfSPZ(PfSPZ Challenges)，这种药物在通过针头和注射器注射给人时完全具有传染性，涉及含氯喹的传染性PfSPZ(PfSPZ CVac)的试验预计将于2012年在美国和欧洲开始。进行PvSPZ-CVac的临床试验将需要投资为PvSPZ开发一种独特的GMP制造。在投资于此类开发之前，在动物模型中获得PvSPZ-CVac的概念证据数据将是有用的。这只能在非人类灵长类动物身上完成，因为PvSPZ不会感染任何其他动物。因此，在制造cGMP依从性材料用于临床试验之前，我们建议评估PvSPZ-CVAc对赛米里猕猴的保护效果。我们将首先确定冷冻保存的PvSPZ的最小感染剂量，然后进行免疫原性和保护效果研究。这些数据将使我们深入了解我们低温保存的PvSPZ在体内的传染性、PvSPZ-CVac的保护效果以及保护的免疫机制。它们可能会提供一种可用于人类的免疫相关保护，并为更好地设计人类PvSPZ疫苗的免疫方案提供信息。

DESCRIPTION (provided by applicant): Plasmodium vivax (Pv) is the 2nd most important human malaria parasite, causing > 80 million cases annually. However, efforts to prevent and control Pv malaria face major challenges of drug resistance and repeated relapses from dormant forms. Moreover, Pv vaccine development has been impeded, because Pv parasites cannot be grown in continuous in vitro culture. Having manufactured the only purified, cryopreserved, vialed P. vivax (Pv) sporozoites (SPZ) in the world, and showed that these cryopreserved PvSPZ can be used to infect a chimpanzee and to infect hepatocytes in vitro, Sanaria is now poised to use these infectious PvSPZ as a first- ever whole parasite vaccine against Pv. The strategy capitalizes on the success of one of only two approaches that have ever induced long-lasting immunity against Pf malaria in humans, one using radiation-attenuated and the other using non-attenuated fully infectious SPZ with chloroquine. In a seminal paper it was shown that immunization by the bite of mosquitoes carrying fully infectious Plasmodium falciparum sporozoites (PfSPZ) of volunteers taking chloroquine induced 100% protective immunity, and protection was still present at 28 months after last immunization. Sanaria's unique technology platform has allowed an immediate translation of this observation with the manufacture of cryopreserved infectious PfSPZ (PfSPZ Challenge) that are fully infectious when administered by needle and syringe to humans, and trials involving infectious PfSPZ with chloroquine (PfSPZ CVac) are expected to begin in the U.S. and Europe in 2012. Conducting clinical trials of PvSPZ-CVac will require investment in development of a unique GMP manufacturing for PvSPZ. Prior to investing in such development, it would be useful to obtain proof of concept data for PvSPZ-CVac in an animal model. This can only be done in non-human primates, as PvSPZ do not infect any other animals. Therefore, before manufacturing cGMP-compliant material for clinical trials, we propose to assess the protective efficacy in Saimiri boliviensis monkeys of PvSPZ-CVac. We will first establish a minimum infective dose for cryopreserved PvSPZ and subsequently carry out immunogenicity and protective efficacy studies. Together the data generated will provide insight into the in vivo infectivity of our cryopreserved PvSPZ, the protective efficacy of PvSPZ-CVac, and the immune mechanisms of protection. They will potentially provide an immune correlate of protection that can be used in humans, and inform better design of an immunization regimen for a PvSPZ vaccine for humans.