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: 10353401
• 负责人: Christopher L King
• 金额: $ 70.67万
• 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/10353401
• 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; Persons; 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; 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; rational design; receptor; receptor binding; sample fixation; transmission process; vaccine development; vaccine strategy; 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.

我们建议的目标是开发预防和治疗人类疟疾的新方法。 由间日疟原虫(P.vivax)引起。这种类型的疟疾，被称为间日疟疾，是最 分布广泛的疟疾类型，全球有33亿人面临风险，至少有1500万临床病例 每年。作为撒哈拉以南非洲以外最常见的疟疾形式，它可以导致严重的疾病和 世界上很大一部分人口死亡。大多数人通过反复接触间日疟原虫 随着时间的推移，感染会获得部分免疫力。这种免疫在一定程度上是由获得性抗体(Abs)介导的 基本的寄生虫蛋白质，可以阻止寄生虫入侵肝脏和红细胞，从而防止 感染，如果被感染，则降低疾病风险。这项提议旨在分离人的单抗。 (单抗)来自对间日疟有免疫力的人，识别一些已知的关键分子 对肝脏和红细胞的入侵是必不可少的。一旦分离，这些单抗将被评估是否 它们在体外和体内用小鼠模型和遗传学方法阻止寄生虫对肝脏和红细胞的入侵 修改过的寄生虫。具有强大封闭活性的单抗将进一步表征到底是如何 以及它们与寄生虫蛋白的相互作用，以及不同种群中的个体是否也有 相同或相似的抗体。这些信息可以用来帮助设计针对间日疟的疫苗。 这些单抗还可用于治疗重病患者，或随着时间的推移预防间日疟， 因为单次注射修饰的单抗可持续数周甚至数月。