Chloroquine Sensitive Plasmodium falciparum for MultiValent Vaccine & Challenge

描述(申请人提供)：消灭恶性疟原虫(PF)的理想工具是一种高效的疫苗，它是99%的疟疾死亡病例的病因，完全 预防血液期感染，从而防止所有疾病和传播。Sanaria的目标是开发一种PF子孢子(SPZ)疫苗并将其商业化，以防止80%的接受者感染PF血液期。Sanaria开发了一种由减毒、纯化、无菌、冷冻保存的PfSPZ组成的疫苗，PfSPZ疫苗是基于对氯喹敏感的PF NF54株。给人体志愿者皮内(ID)、皮下(SC)或静脉(IV)注射是安全和耐受性良好的(1)。当静脉注射时，它具有高度的免疫原性和对同源控制的人类疟疾感染(CHMI)的高水平保护(100%)(R.Seder等人，在准备中)。Roestenberg和他的同事(2)已经独立展示了通过蚊子叮咬给氯喹治疗的志愿者使用非减毒NF54 PfSPZ的高水平(100%)、长期(28个月)的保护，这种方法被称为用子孢子进行化学预防(CPS)。我们已经实现了PfSPZ身份注射(称为PfSPZ挑战)(3)志愿者的成功感染，最近通过静脉注射3200 PfSPZ(Mordmueller，在准备中)感染了100%的志愿者(9/9)。PfSPZ挑战赛的这些发现建立了将CPS快速转化为一种实用疫苗方法的方法，称为PfSPZ-CVAc，在该方法中，PfSPZ挑战赛使用氯喹化学预防。PfSPZ-CVAC的第一次临床试验目前正在进行中。虽然有限的现有证据表明，整个PfSPZ免疫可以诱导对同源和异源CHMI攻击的保护，但我们认为，由至少3株不同地理来源的PF毒株组成的多价疫苗将最好地确保全球保护。我们在这个项目中的目标是确定可用于以下用途的PF氯喹敏感株：1)在CHMI中评估基于PfSPZ的疫苗的广谱疗效；2)如果需要，将这些毒株包括在多价疫苗成分中，以实现广泛的疗效。为了实现这一目标，我们将适应至少2株来自非洲和亚洲的氯喹敏感的PF菌株的连续培养，这些菌株表现出适合Sanaria的PfSPZ制造工艺的无性生长和有性阶段和产孢子发育特征。在过去的30年里，只建立了几个能够从培养的配子细胞中产生适当丰富的PfSPZ的寄生虫菌株。实现我们的目标将需要Sanaria独特的工业化方法来生产PfSPZ，包括在Sanaria的研发设施中对多种氯喹敏感寄生虫菌株进行系统筛选，在该研发设施中，配子体培养、蚊子感染、PfSPZ提取和定量分析都会持续进行。使用异源PF毒株测试异种保护效力并启动多价疫苗制造的能力可以将PfSPZ疫苗的上市时间缩短至少2年，从而节省数千万至数亿美元的成本。

DESCRIPTION (provided by applicant): The ideal tool for eliminating Plasmodium falciparum (Pf), the causative agent of 99% of all malaria deaths, is a highly effective vaccine that entirely prevents blood stage infection and thereby prevents all disease and transmission. Sanaria's goal is to develop and commercialize a Pf sporozoite (SPZ) vaccine that prevents Pf blood stage infection in > 80% of recipients. Sanaria developed a vaccine composed of attenuated, purified, aseptic, cryopreserved PfSPZ, the PfSPZ Vaccine based on the chloroquine-sensitive NF54 strain of Pf. It is safe and well-tolerated when administered to human volunteers by intradermal (ID), subcutaneous (SC) or intravenous (IV) injection (1). It is highly immunogenic and conferred high level protection (100%) against homologous controlled human malaria infection (CHMI) when administered IV (R. Seder et al., in prep.). Roestenberg and co-workers (2) have independently demonstrated high level (100%), long-lasting (28 months) protection with non-attenuated NF54 PfSPZ administered to chloroquine-treated volunteers by the bites of mosquitoes, an approach referred to as chemoprophylaxis with sporozoites (CPS). We have achieved successful infection of volunteers with ID administration of PfSPZ (called PfSPZ Challenge) (3), and recently infected 100% of volunteers (9/9) with IV administration of 3,200 PfSPZ (Mordmueller, in prep.). These findings with PfSPZ Challenge establish the means to rapidly translate CPS into a practical vaccine approach, termed PfSPZ-CVac, in which PfSPZ Challenge is administered with chloroquine chemoprophylaxis. The first clinical trial of PfSPZ-CVac is now in progress. While the limited available evidence suggests that whole PfSPZ immunization can induce protection against homologous and heterologous CHMI challenge, we assume that a multivalent vaccine composed of at least 3 Pf strains of diverse geographic origin will best insure worldwide protection. Our goal in this project is to identify chloroquine sensitiv strains of Pf that can be used: 1) in CHMI to assess the broad-spectrum efficacy of PfSPZ-based vaccines and 2) if there is a need, to include these strains as multivalent vaccine components to achieve broad efficacy. To accomplish this we will adapt to continuous culture at least 2 chloroquine sensitive strains of Pf from Africa and Asia that exhibit asexual growth and sexual stage and sporogonic development characteristics suitable for Sanaria's PfSPZ manufacturing process. During the past 30 yrs, only a few parasite strains have been established that are capable of producing suitably abundant PfSPZ from cultured gametocytes. Achieving our aims will require Sanaria's unique, industrialized approach to PfSPZ production, including systematic screening of multiple chloroquine sensitive parasite isolates in Sanaria's R&D facility where gametocyte culture, mosquito infection, and PfSPZ extraction and quantitative analysis is carried out continuously. The ability to test heterologous protective efficacy and initiate multivalent vaccine manufacturing using heterologous Pf strains could reduce the time to market for PfSPZ vaccines by at least 2 years, with cost savings of tens to hundreds of millions of dollars.