Safety and efficacy of PfSPZ malaria vaccine in malaria-exposed adults

描述（由申请人提供）：一种高效阻断恶性疟原虫感染的疟疾疫苗也将预防疟疾传播，改善区域疟疾消除和最终全球根除的前景。通过暴露于携带放射减毒的恶性疟原虫子孢子的蚊子对人类进行免疫，保护>90%的志愿者免受实验性恶性疟原虫攻击。我们在Sanaria Inc.的合作伙伴已经开发了一种用于获得纯化的恶性疟原虫子孢子的制造方法，所述子孢子用于通过针注射给人施用。本品为“PfSPZ疫苗”，在无菌饲养的斯氏按蚊成虫中生产，这些蚊喂食含有无菌恶性疟原虫配子体的血培养物。在受感染的蚊子被照射以减毒子孢子之后，这些经辐射减毒的子孢子被分离、纯化，并且最终产物被冷冻保存。最近的一项研究发现，PfSPZ疫苗的五个静脉注射（IV）剂量在最高剂量组中具有100%的保护效力。要确定这种疫苗的效用，必须克服的障碍包括评估其对疟疾流行人群中遗传多样性天然寄生虫的安全性和有效性，以及减少达到高度保护所需的剂量。我们的目标是在疟疾流行的布基纳法索Balonghin进行的一项随机、双盲、安慰剂对照、剂量递增的1期临床试验中推进这种疫苗的临床开发。为了评价子孢子总剂量以及给药次数和时间对既存抗疟免疫人群免疫原性和疗效的重要性，我们将使用NIH研究中提供100%疗效的总累积剂量的两倍，以比较该研究中使用的相同给药方案与间隔8周或12周的三次给药。90名健康成人将入组3个队列，每组30名，并以2：1的比例随机分配至每个队列 队列接受递增剂量的PfSPZ或安慰剂。将评价安全性和耐受性、体液和细胞介导的免疫以及总体和菌株特异性疗效的探索性指标。这将是第一次在生活在疟疾流行地区的疟疾患者中确定这种有前途的疟疾候选疫苗的安全性和耐受性的临床试验，也是第一次评估PfSPZ疫苗对自然界中多种恶性疟原虫菌株的有效性。如果成功，这项试验将推动疫苗的临床开发，该疫苗旨在通过大规模免疫从地理上确定的地区消除疟疾，并在疟疾流行地区的非免疫游客，如游客和商业，援助，外交和军事人员中预防疟疾。免疫学和寄生虫基因组终点的探索将促进我们对疫苗诱导的疟疾保护性免疫的理解，并有助于确定是否以及如何开发多株子孢子疫苗，以提供对遗传多样性疟疾寄生虫的广泛保护。

DESCRIPTION (provided by applicant): A malaria vaccine that blocks infection by Plasmodium falciparum with high efficacy would also prevent malaria transmission, improving prospects for regional malaria elimination and eventual global eradication. Immunization of humans by exposure to mosquitoes carrying radiation-attenuated P. falciparum sporozoites protects >90% of volunteers against experimental P. falciparum challenge. Our collaborators at Sanaria Inc. have developed a manufacturing process for obtaining purified P. falciparum sporozoites for human administration by needle injection. This product, the "PfSPZ Vaccine", is produced in aseptically raised adult Anopheles stephensi mosquitoes fed on blood cultures containing aseptic P. falciparum gametocytes. After infected mosquitoes are irradiated to attenuate the sporozoites, these radiation-attenuated sporozoites are isolated, purified, and the final product is cryopreserved. A recent study found that five intravenous (IV) doses of the PfSPZ Vaccine had 100% protective efficacy in the highest dose group. Obstacles that must be overcome to establish the utility of this vaccine include assessment of its safety and efficacy against genetically diverse natural parasites in malaria-endemic populations, and diminishing the number of doses required to achieve high protection. We aim to advance the clinical development of this vaccine in a randomized, double-blind, placebo-controlled dose escalation Phase 1 clinical trial in Balonghin, Burkina Faso, where malaria is endemic. To evaluate the importance of total sporozoite dose and number and timing of doses to immunogenicity and efficacy in a population with pre-existing antimalarial immunity, we will use twice the total cumulative dose that provided 100% efficacy in the NIH study to compare the same dosing schedule used in that study against three doses spaced either 8 or 12 weeks apart. Ninety healthy adults will be enrolled into three cohorts of 30, and randomized in a 2:1 ratio within each cohort to receive escalating doses of PfSPZ or placebo. Safety and tolerability, humoral and cell-mediated immunity, and exploratory measures of overall and strain-specific efficacy will be evaluated. This will be the first clinical trial to establish safety and tolerability of this promiing malaria candidate vaccine in malaria-experienced individuals living in a malaria-endemic area, and the first evaluation of the efficacy of PfSPZ Vaccine against diverse P. falciparum strains that occur in nature. If successful, this trial will advance the clinical development of a vaccine intended to eliminate malaria from geographically defined areas through mass immunization and to prevent malaria in non-immune visitors to malarious areas, such as tourists and business, aid, diplomatic and military personnel. The exploration of immunological and parasite genomic endpoints will advance our understanding of vaccine-induced protective immunity to malaria and help to determine whether and how a multi-strain sporozoite vaccine should be developed to provide broad protection against genetically diverse malaria parasites.