Multi-target blood stage vaccine against Plasmodium falciparum

抗恶性疟原虫的多靶点血期疫苗

• 批准号: 9886984
• 负责人: Dipak Kumar Raj
• 金额: $ 40万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-13 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9886984
• 关键词: 2 year old; 5 year old; Achievement; Adjuvant; Adjuvant Study; Affect; Africa; Africa South of the Sahara; Alhydrogel; Animals; Antibodies; Antibody titer measurement; Antigens; Aotus primate; Area; B-Cell Development; B-Lymphocytes; BALB/cJ Mouse; Biological Assay; Birth; Blocking Antibodies; Blood; Cells; Cerebral Malaria; Cessation of life; Child; Childhood; Chimeric Proteins; Clinical; Complementary DNA; Country; Data; Development; Disease; Dose; Encapsulated; Enzyme-Linked Immunosorbent Assay; Erythrocytes; Evaluation; Falciparum Malaria; Formulation; Future; Generations; Genes; Glutamic Acid; Gold; Growth; Growth and Development function; Helper-Inducer T-Lymphocyte; Hemoglobin concentration result; Human; Immune system; Immunize; Immunodominant Epitopes; In Vitro; Individual; Infection; Laboratories; Lead; Legal patent; Length; Libraries; Life Cycle Stages; Ligands; Lipids; Malaria; Malaria Vaccines; Measures; Memory B-Lymphocyte; Messenger RNA; Methods; Modeling; Monkeys; Morbidity - disease rate; Mus; Orthologous Gene; Parasitemia; Parasites; Parasitic Diseases; Pathway interactions; Phage Display; Phase; Phase I Clinical Trials; Planets; Plants; Plasma; Plasmodium falciparum; Population; Primates; Process; Proteins; Proteome; Publications; Publishing; Regulatory T-Lymphocyte; Research; Resistance; Rodent; Rupture; Science; Side; Site; Surface; System; Tanzania; TiterMax; Vaccinated; Vaccination; Vaccines; Work; asexual; base; cDNA Library; calcium-dependent protein kinase; cell mediated immune response; cohort; density; disorder control; epidemiologic data; in vitro Assay; mortality; mouse model; nonhuman primate; novel; novel vaccines; polyclonal antibody; primary outcome; programs; response; screening; secondary outcome; success; synergism; trial design; vaccine candidate; vaccine discovery; vaccine efficacy; vaccine trial

Project Summary The overall aim of this application is to advance PfCDPK5 and PfGARP as vaccine candidates for falciparum malaria. P.falciparum malaria affects almost one-half of the world's population and causes more than 500,000 deaths annually. Young children in malaria endemic areas of Africa have the highest mortality rate because of their immature immune systems. Global efforts to control the disease have had limited success, and no vaccine has yet been approved for clinical use. Therefore, there is an urgent, unmet need to discover new vaccine candidates. A vaccine against childhood malaria is a priority because children below the age of 5 years are highly vulnerable to the disease. In recent studies, our laboratory discovered Schizont Egress Antigen-1 (PfSEA-1), a 244-kDa-parasite antigen that is crucial for parasite egress from an infected red blood cell (iRBC), which was published as a comprehensive, full-length Research Article in Science. In a parallel approach, we have screened phage display cDNA libraries constructed from parasites isolated at our Tanzanian field site with/without culture adaptation using positive selection with antibodies pooled from resistant two-year-olds and negative selection with antibodies pooled from susceptible children. We identified several independent cDNA clones encoding plasmodium falciparum glutamic acid reach protein (PfGARP) and plant-like calcium-dependent protein kinase (PfCDPK5) that were uniquely recognized by antibodies in resistant, but not susceptible sera. Our preliminary data demonstrate that PfGARP and PfCDPK5 is critical for parasite development in side RBC and egress respectively). PfGARP expresses on the surface of the trophozoite infected RBC and PfCDPK5 is expressed by merozoites as they rupture from erythrocytes. Antibodies against PfGARP and PfCDPK5 block parasite growth up to 99% in vitro, and ortholog vaccine of CDPK5 protect mice from parasitemia, and extend the survival of mice challenged with lethal P. berghei ANKA. Our vaccine discovery program has also identified several known invasion ligands (MSP-4 and MSP-7 collectively referred to as MSPs) In this application, we will evaluate these vaccine candidates with CDPK5 as single fusion protein (PfCDPK5-MSP4 & PfCDPK5-MSP7) in combination with PfGARP in in vitro assays and using multiple adjuvant systems in murine vaccine trials. The lead fusion antigen will be further evaluated for cell mediated immune response using TFRS depletion method in murine model. The deliverables from this study will be an adjuvant optimized tri-valent vaccine ready for Aotus/ P. falciparum challenge and Phase-1 clinical trial in human that targets the entry, intracellular development, and the exit of the parasite cycle in .

项目摘要 该应用程序的总体目的是推进PFCDPK5和PFGARP作为候选疫苗 恶性疟疾。疟原虫疟疾影响了世界上几乎一半的人口，并导致更多 每年超过500,000人死亡。非洲疟疾流行地区的幼儿死亡率最高 由于其不成熟的免疫系统而速率。全球控制这种疾病的努力限制了 成功，尚无疫苗用于临床用途。因此，紧急，未满足的需要 发现新的候选疫苗。针对儿童疟疾的疫苗是优先事项，因为 5岁的年龄非常容易受到这种疾病的影响。在最近的研究中，我们的实验室发现了Schizont 出口抗原-1（PFSEA-1），一种244 kDa-寄生虫抗原，对于从感染的红色的寄生虫出口至关重要 血细胞（IRBC）作为科学的全面，全长研究文章发表。 在平行的方法中，我们已经筛选了由寄生虫构建的噬菌体显示cDNA库 在我们的坦桑尼亚现场分离，使用抗体阳性选择，具有/不具有培养的适应性 由耐药的两岁儿童汇集，并从易感儿童中汇集的抗体进行负选择。 我们确定了编码恶性疟原虫谷氨酸到达蛋白的几个独立的cDNA克隆 （PFGARP）和类似植物的钙依赖性蛋白激酶（PFCDPK5），这些蛋白激酶被独特地识别 抗体中的抗体，但不易感血清。我们的初步数据表明PFGARP和PFCDPK5 分别对RBC和出口侧的寄生虫发育至关重要）。 pfgarp在表面表达 滋养体感染的RBC和PFCDPK5在红细胞中破裂时用蛋白酶表达。 抗PfGARP和PFCDPK5寄生虫生长的抗体在体外高达99％，而直系同源疫苗 CDPK5可保护小鼠免受寄生虫病的影响，并扩大了受致命的伯格（P. Berghei Anka）挑战的小鼠的存活。 我们的疫苗发现计划还确定了几种已知的入侵配体（MSP-4和MSP-7 在此应用程序中，我们将共同称为MSP），我们将用CDPK5评估这些疫苗候选者 单融合蛋白（PFCDPK5-MSP4和PFCDPK5-MSP7）与PFGARP在体外测定中结合 在鼠疫苗试验中使用多个辅助系统。将进一步评估铅融合抗原 在鼠模型中使用TFRS耗竭法的细胞介导的免疫反应。这项研究的可交付成果 将是一种辅助优化的三价疫苗 针对进入，细胞内发育和寄生虫周期的出口的人类试验。