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

描述(由申请人提供)：一种能高效阻断恶性疟原虫感染的疟疾疫苗也将防止疟疾传播，改善区域消除疟疾和最终全球根除的前景。通过暴露于携带辐射减毒恶性疟原虫子孢子的蚊子对人类进行免疫，可保护90%的志愿者免受实验性恶性疟原虫的攻击。我们在Sanaria Inc.的合作者开发了一种生产工艺，通过针头注射获得纯化的恶性疟原虫子孢子，供人类使用。这种名为“PfSPZ疫苗”的产品是在无菌饲养的斯氏按蚊成年蚊子中生产的，喂养的是含有无菌恶性疟原虫配子体的血液培养物。在被感染的蚊子被辐射减毒后，这些被辐射减毒的子孢子被分离、纯化，并将最终产品冷冻保存。最近的一项研究发现，静脉注射5剂PfSPZ疫苗在最高剂量组具有100%的保护效果。要建立这种疫苗的效用，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自然寄生虫的安全性和有效性，以及减少实现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巴隆欣进行一项随机、双盲、安慰剂控制的剂量递增第一阶段临床试验，以推进这种疫苗的临床开发。为了评估子孢子的总剂量、剂量的数量和时间对已有抗疟免疫的人群的免疫原性和有效性的重要性，我们将使用NIH研究中提供100%疗效的总累积剂量的两倍，将该研究中使用的相同剂量方案与间隔8周或12周的三种剂量进行比较。90名健康成年人将被分成三组，每组30人，并按2：1的比例随机分组 接受剂量递增的PfSPZ或安慰剂的队列。将评估安全性和耐受性、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措施。这将是第一次在疟疾流行地区有疟疾经验的个人中确定这种临时候选疟疾疫苗的安全性和耐受性的临床试验，也将是第一次评估PfSPZ疫苗对自然界中出现的各种恶性疟原虫菌株的有效性。如果成功，这项试验将推进疫苗的临床开发，旨在通过大规模免疫从地理上确定的地区消除疟疾，并在前往疟疾地区的非免疫游客，如游客和商业、援助、外交和军事人员中预防疟疾。对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毒株子孢子疫苗，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.