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

PfSPZ 疟疾疫苗对疟疾暴露成人的安全性和有效性

• 批准号: 8989966
• 负责人: CHRISTOPHER V. PLOWE
• 金额: $ 62.66万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8989966
• 关键词: Adult; Adverse event; Africa South of the Sahara; African; Anopheles Genus; Antibodies; Antigens; Antimalarials; Area; Attenuated; Blood; Burkina Faso; Businesses; Candidate Disease Gene; Cellular Immunity; Characteristics; Clinical; Clinical Trials; Control Groups; Culicidae; Detection; Development; Diagnostic; Dose; Double-Blind Method; Enrollment; Erythrocytes; Evaluation; Exposure to; Future; Genetic Variation; Genomics; Genotype; Goals; Haplotypes; Health; Human; Immune; Immune response; Immunity; Immunization; Individual; Infection; Injection of therapeutic agent; Intravenous; Licensing; Life; Life Cycle Stages; Liver; Malaria; Malaria Vaccines; Mass Immunization; Measures; Military Personnel; Nature; Needles; Nucleic Acids; Parasites; Participant; Peripheral Blood Mononuclear Cell; Phase I Clinical Trials; Placebo Control; Placebos; Plasmodium falciparum; Plasmodium falciparum vaccine; Population; Proteins; Public Health; Quantitative Microscopy; Radiation; Randomized; Reaction; Role; Safety; Schedule; Serious Adverse Event; Serum; Shapes; Sporozoite vaccine; Sporozoites; Staging; T cell response; T-Lymphocyte; Testing; Time; United States National Institutes of Health; Vaccinated; Vaccination; Vaccines; Variant; cohort; economic impact; efficacy evaluation; experience; exposed human population; feeding; genome-wide; health economics; immunogenicity; improved; malaria infection; malaria transmission; manufacturing process; prevent; protective efficacy; response; tool; vaccine candidate; vaccine development; vaccine efficacy; vaccine safety; volunteer

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.

描述（由申请人提供）：一种疟疾疫苗，可阻止恶性疟原虫具有高疗效的感染，这也将防止疟疾传播，从而改善了局部疟疾消除和最终全球消除的前景。通过暴露于携带辐射降低的恶性疟原虫孢子虫的蚊子来保护人类的免疫接种，可保护> 90％的志愿者免受实验性恶性疟原虫的挑战。我们在Sanaria Inc.的合作者开发了一种制造过程，用于通过针注射获得纯化的恶性疟原虫孢子虫用于人类管理。该产品是“ PFSPZ疫苗”，是在无菌的成年蚊子斯蒂芬斯蚊子中产生的，这些蚊子是在含有无菌性恶性疟原虫配子细胞的血液培养物上产生的。辐照感染的蚊子以减弱孢子虫时，将这些辐射衰减的子孢子分离，纯化，最终产物被冷冻保存。最近的一项研究发现，PFSPZ疫苗的五种静脉内（IV）剂量在最高剂量组中具有100％的保护效果。确定该疫苗实用性必须克服的障碍包括评估其对疟疾流行种群中遗传多样性自然寄生虫的安全性和功效，以及减少获得高保护所需的剂量的数量。我们旨在在随机的，双盲的，安慰剂控制的剂量升级阶段1临床试验中，在疟疾是地方性的Balonghin，在Balonghin的临床中提高该疫苗的临床开发。为了评估孢子虫剂量总剂量以及剂量的数量和时间对免疫原性和疗效的数量和疗效的时间，我们将使用两倍的总累积剂量，这些总累积剂量在NIH研究中提供了100％的效率，以比较该研究中的三剂剂量时间表，以比较三剂剂量的剂量，以比较三剂剂量分隔了8或12周。 90名健康的成年人将被招募成30个队列，并在每个人中以2：1的比例随机分配 队列接受不断升级的PFSPZ或安慰剂。将评估安全性和耐受性，体液和细胞介导的免疫力以及总体和应变特异性功效的探索性措施。这将是首次在疟疾经验的人群中建立这种有可能的疟疾候选疫苗的安全性和耐受性的临床试验，并且首次评估了PFSPZ疫苗针对自然界中发生的多种恶性疟原虫菌株的疗效。如果成功，该试验将推进旨在通过大规模免疫从地理定义的地区消除疟疾的疫苗的临床开发，并防止非免疫访客疟疾到疟疾地区，例如游客和商业，援助，外交和军事人员。免疫和寄生虫基因组终点的探索将提高我们对疫苗诱导的对疟疾的保护性免疫的理解，并有助于确定是否应以及如何开发多菌种孢子岩疫苗，以提供对遗传多样的疟疾寄生虫的广泛保护。