Multi-target blood stage vaccine against Plasmodium falciparum

抗恶性疟原虫的多靶点血期疫苗

基本信息

批准号：
10554696
负责人：
Dipak Kumar Raj
金额：
$ 36.88万
依托单位：
UNIVERSITY OF SOUTH FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-13 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10554696
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 antibody test 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 evaluation vaccine trial

项目摘要

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 .

项目概要该申请的总体目标是推动 PfCDPK5 和 PfGARP 作为候选疫苗恶性疟疾。恶性疟原虫疟疾影响着世界上近一半的人口，并导致更多每年死亡人数超过 50 万人。非洲疟疾流行区幼儿死亡率最高因为他们的免疫系统不成熟。全球控制该疾病的努力收效有限成功，但尚未批准任何疫苗用于临床。因此，存在迫切且尚未满足的需求发现新的候选疫苗。儿童疟疾疫苗是当务之急，因为年龄以下的儿童 5岁以下儿童极易感染该病。在最近的研究中，我们的实验室发现了裂殖体 Egress Antigen-1 (PfSEA-1)，一种 244 kDa 的寄生虫抗原，对于寄生虫从受感染的红色病毒中排出至关重要血细胞 (iRBC)，该文章作为一篇全面、完整的研究文章发表在《科学》杂志上。在并行方法中，我们筛选了由寄生虫构建的噬菌体展示 cDNA 文库在我们的坦桑尼亚现场进行分离，使用抗体正选进行培养适应/不适应培养从耐药的两岁儿童中收集，并用从易感儿童中收集的抗体进行阴性选择。我们鉴定了几个编码恶性疟原虫谷氨酸到达蛋白的独立 cDNA 克隆 (PfGARP) 和植物样钙依赖性蛋白激酶 (PfCDPK5) 被独特地识别抗性血清中存在抗体，但不敏感血清中存在抗体。我们的初步数据表明 PfGARP 和 PfCDPK5 分别对于红细胞侧部和出口处的寄生虫发育至关重要）。 PfGARP 表达于表面滋养体感染的红细胞和 PfCDPK5 在裂殖子从红细胞破裂时表达。 PfGARP 和 PfCDPK5 抗体在体外可阻止寄生虫生长高达 99%，并且 CDPK5 保护小鼠免受寄生虫血症，并延长遭受致命伯氏疟原虫 ANKA 攻击的小鼠的存活时间。我们的疫苗发现计划还鉴定了几种已知的入侵配体（MSP-4 和 MSP-7）统称为 MSP）在此应用中，我们将使用 CDPK5 评估这些候选疫苗：单一融合蛋白（PfCDPK5-MSP4 和 PfCDPK5-MSP7）在体外试验中与 PfGARP 组合，在鼠疫苗试验中使用多种佐剂系统。将进一步评估先导融合抗原在小鼠模型中使用 TFRS 消耗方法进行细胞介导的免疫反应。本研究的成果将是一种佐剂优化的三价疫苗，可用于 Aotus/ 恶性疟原虫挑战和 1 期临床人体试验，针对寄生虫循环的进入、细胞内发育和退出。