Defining targets of protective immunity to vivax malaria using human monoclonal antibodies

使用人单克隆抗体确定间日疟疾的保护性免疫目标

• 批准号: 9973847
• 负责人: Christopher L King
• 金额: $ 77.43万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-24 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9973847
• 关键词: Address; Adjuvant; Adult; Affinity; Africa South of the Sahara; Amino Acid Sequence; Antibodies; Antigens; Area; B-Lymphocytes; Binding Proteins; Biological Assay; Biomass; Blood; Brazil; Cambodia; Cells; Cessation of life; Child; Chimeric Proteins; Chronic; Clinical; Clone Cells; Complement; Copy Number Polymorphism; Data; Development; Drug resistance; Epitopes; Erythrocytes; Ethiopia; Event; Exposure to; Fever; Gene Dosage; Genetic Polymorphism; Geography; Goals; Health Policy; Hepatic; Hepatocyte; Human; Immune; Immune Sera; Immunity; Immunize; Immunoglobulin G; Immunologist; In Vitro; Individual; Infection; Infection prevention; Injections; Knowledge; Liver; Longitudinal cohort; Lymphocyte; Malaria; Malaria Vaccines; Measures; Mediating; Monoclonal Antibodies; Morbidity - disease rate; Papua New Guinea; Parasites; Patients; Plasmodium falciparum; Plasmodium vivax; Plasmodium vivax vaccine; Play; Population; Population Heterogeneity; Prevention; Prevention approach; Primary Infection; Production; Proteins; Public Health; Relapse; Residual state; Reticulocytes; Risk; Role; Solomon Islands; Sporozoites; Structure; Syndrome; Technology; Time; Transcend; Transgenic Organisms; Vaccines; Vivax Malaria; Work; apical membrane; circumsporozoite protein; design; disorder risk; experimental study; human monoclonal antibodies; in vitro Assay; in vivo; innovation; migration; mouse model; neutralizing monoclonal antibodies; next generation; novel strategies; novel therapeutics; novel vaccines; parasite invasion; prevent; receptor; receptor binding; sample fixation; transmission process; vaccine development; vaccine-induced immunity

The goal of our proposal is to develop new approaches for the prevention and treatment of human malaria caused by the parasite Plasmodium vivax (P. vivax). This type of malaria, known as vivax malaria, is the most widely distributed type of malaria with 3.3 billion people at risk and at least 15 million clinical cases worldwide each year. As the most common form of malaria outside sub-Saharan Africa, it can cause severe illness and death across a large segment of the world's population. Most individuals exposed to P. vivax through repeated infection gain partial immunity over time. The immunity is mediated, in part, by acquired antibodies (Abs) to essential parasite proteins that can block the parasite invasion into liver and red blood cells thereby preventing infection and if infected reduce the risk of disease. This proposal aims to isolate human monoclonal antibodies (mAbs) from individuals with immunity to vivax malaria that recognize a few key molecules known to be essential for invasion of liver and red blood cells. Once isolated these mAbs will be evaluated as to whether they block parasite invasion of liver and red cells in vitro, and in vivo using murine models and genetically modified parasites. Monoclonal Abs with potent blocking activity will be further characterized as to exactly how and where they interact with parasite proteins and whether individuals in diverse populations also have the same or similar antibodies. This information can be used to help to design a vaccine against vivax malaria. These mAbs can also be used for treatment of severely ill patients, or for prevention of vivax malaria over time, since a single injection of modified mAbs can last for weeks and even months.

我们建议的目的是开发预防和治疗人类疟疾的新方法 由寄生虫疟原虫（Vivax）引起。这种类型的疟疾，称为Vivax疟疾，是最多的 疟疾的分布广泛，有33亿人有危险的人和全球至少1500万个临床病例 每年。作为撒哈拉以南非洲以外的疟疾最常见的形式，可能会导致严重疾病和 世界人口的大部分地区死亡。大多数人通过重复暴露于Vivax 随着时间的流逝，感染会获得部分免疫力。免疫是通过获得的抗体（ABS）介导的 必需的寄生虫蛋白可以阻止寄生虫入侵肝脏和红细胞，从而阻止 感染和如果感染减少了疾病的风险。该建议旨在隔离人类单克隆抗体 （mAb）从免疫力到识别一些已知的关键分子的个体到疟疾 肝脏和红细胞入侵必不可少的。一旦隔离了这些mab，将评估是否 它们在体外阻止了肝脏和红细胞的寄生虫侵袭，并使用鼠模型和遗传学上的体内侵袭了体内 修饰的寄生虫。单克隆ABS具有有效的阻塞活性，将进一步表征 以及他们与寄生虫蛋白相互作用的地方以及不同人群中的个人是否也有 相同或相似的抗体。该信息可用于帮助设计针对Vivax疟疾的疫苗。 这些mAB也可用于治疗严重患者，或者随着时间的流逝预防病毒疟疾， 由于单次注射改良的mAb可以持续数周甚至几个月。