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，改善区域消灭疟疾和最终全球消灭疟疾的前景。通过接触携带辐射减毒的恶性疟原虫孢子虫的蚊子，对人类进行免疫接种，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公司的合作伙伴已经开发了一种生产工艺，可以通过针注射获得纯化的恶性疟原虫孢子体。这种产品，即“PfSPZ疫苗”，是在无菌饲养的成年斯氏按蚊中生产的，这些蚊子以含有无菌恶性疟原虫配子细胞的血液培养物为食。在对受感染的蚊子进行辐照以减弱孢子虫后，将这些辐射减弱的孢子虫分离、纯化，并将最终产物冷冻保存。最近的一项研究发现，在最高剂量组中，五次静脉注射（IV）剂量的PfSPZ疫苗具有100%的保护功效。为确定这种疫苗的效用，必须克服的障碍包括评估其在疟疾流行人群中对遗传多样性天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、安慰剂对照剂量递增的1期临床试验，推动这种疫苗的临床开发。为了评估孢子囊总剂量、剂量数量和剂量时间对预先存在抗疟疾免疫的人群免疫原性和有效性的重要性，我们将使用NIH研究中提供100%有效性的总累积剂量的两倍来比较该研究中使用的相同给药方案和间隔8或12周的三次给药。90名健康成人将被纳入3组，每组30人，并按2:1的比例随机分组

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.