PfSEA-1 based vaccines for falciparum malaria

基于 PfSEA-1 的恶性疟疾疫苗

基本信息

批准号：
9330056
负责人：
Jonathan D. Kurtis
金额：
$ 61.59万
依托单位：
BROWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-16 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9330056
关键词：
2 year old Achievement Active Immunization Adjuvant Adolescent and Young Adult Africa South of the Sahara Alhydrogel Antibodies Antibody titer measurement Antigens Aotus primate Biological Assay Birth Blood Cells Child Chimeric Proteins Combined Vaccines CpG 7909 DNA Data Defect Developing Countries Development Erythrocytes Falciparum Malaria Film Formulation Funding Future Genetic Growth Hemoglobin concentration result Hepatocyte Human Immunize In Vitro Inbred BALB C Mice Incidence Individual Injection of therapeutic agent Intraperitoneal Injections Investigation Lead Length Ligands Malaria Membrane Methods Modeling Monkeys Morbidity - disease rate Mus Organ Outcome Parasitemia Parasites Pathway interactions Phase I Clinical Trials Plasma Plasmodium falciparum Process Production Proteome Research Resistance Rupture Safety Science Splenocyte Tanzania Toxic effect Vaccinated Vaccination Vaccines Vacuole Work base cohort epidemiologic data experience experimental study in vitro Assay killings mortality nonhuman primate novel novel strategies primary outcome programs public health relevance response screening secondary outcome vaccine candidate vaccine discovery vaccine efficacy vaccine trial

项目摘要

DESCRIPTION (provided by applicant): The overall aim of this application is to advance PfSEA-1 as a vaccine candidate for falciparum malaria. P. falciparum malaria is a leading cause of morbidity and mortality in developing countries, infecting hundreds of millions of individuals and killing over one million children in sub-Saharan Africa each year. In previous R01 funded studies, we identified the parasite targets of naturally acquired protective human antibodies. We applied our differential, whole proteome screening method using plasma and epidemiologic data from a birth cohort of children living in Tanzania to identify novel Plasmodium falciparum antigens associated with resistance in two-year old children. This work has culminated in a comprehensive, full length Research Article in Science. We discovered Schizont Egress Antigen-1 (PfSEA-1), a 244-kDa parasite antigen which localizes to the schizont/parasitophorous vacuole membrane, Maurer's clefts and the inner leaflet of the RBC membrane in schizont infected RBCs. Antibodies to a central, highly invariant 274 aa region of PfSEA-1 (rPfSEA-1A, aa 810- 1083) decrease parasite replication by 58-75% across three parasite strains compared to controls (all P < 0.009) by arresting schizont rupture. In genetic destabilization experiments, parasites with destabilized PfSEA- 1 had a marked, 4.9 fold defect in parasite replication (P < 0.001). Active vaccination with rPbSEA-1 results in a 3.9 fold reduction in parasitemia and 2 fold longer survival after challenge with P. berghei ANKA parasites (P = 0.001). Children in our Tanzanian cohort experienced a dramatically increased incidence of severe malaria during periods with undetectable anti-PfSEA-1 antibody levels (45 cases/23,806 child weeks) compared to periods with detectable antibody levels (0 cases/1,688 child weeks; adjusted OR 4.4; Type III fixed effects P < 0.01). Adolescents and young adults in our Kenyan cohort with detectible anti-PfSEA-1 antibodies had 50% lower parasitemia compared to individuals without detectible anti-PfSEA-1 antibodies. These results represent the first demonstration that antibodies that specifically block schizont egress can protect against severe malaria in humans and suggest that PfSEA-1 may synergize with vaccines targeting hepatocyte and red cell invasion. Our vaccine discovery program has also identified several known invasion ligands (MSP-4 and MSP-7 3- collectively referred to as MSPs) and PfGARP, a previously unrecognized vaccine candidate found only in falciparum. In in vitro assays, polyclonal anti-MSP-4 inhibited parasite growth by 22% (P < 0.001) and this inhibition increased to 67% when combined with anti-PfSEA-1 mAb (P < 0.001). Antibodies to the highly invariant carboxyl terminal of PfGARP (PfGARP-A, aa 411-673) inhibited parasite growth in vitro by 99% compared to controls (P < 0.001) by arresting trophozoite development. In this application, we will evaluate combinations of these vaccine candidates in multiple adjuvants in murine vaccine trials and the lead combination will be further evaluated in non-human primates. The deliverables from this study will be an adjuvant optimized tri-valent vaccine that targets the entry, intracellular development, and the exit of the parasite from a single, critical parasite stae.

描述（由申请人提供）：本申请的总体目标是推动 PfSEA-1 作为恶性疟疾的候选疫苗。恶性疟原虫疟疾是发展中国家发病和死亡的主要原因，每年在撒哈拉以南非洲地区感染数亿人并导致超过一百万儿童死亡。在之前的 R01 资助的研究中，我们确定了自然获得的人类保护性抗体的寄生虫靶标。我们利用来自坦桑尼亚出生队列的儿童的血浆和流行病学数据应用差异化全蛋白质组筛查方法来识别与两岁儿童耐药性相关的新型恶性疟原虫抗原。这项工作最终形成了一篇全面、完整的科学研究文章。我们发现了裂殖体出口抗原-1 (PfSEA-1)，这是一种 244 kDa 的寄生虫抗原，定位于裂殖体/寄生泡膜、Maurer 裂和裂殖体感染红细胞中红细胞膜的内叶。与对照相比，针对 PfSEA-1 中心高度不变的 274 个氨基酸区域（rPfSEA-1A，氨基酸 810-1083）的抗体可通过阻止裂殖体破裂，使三种寄生虫品系的寄生虫复制减少 58-75%（所有 P < 0.009）。在遗传不稳定实验中，具有不稳定 PfSEA-1 的寄生虫在寄生虫复制方面具有明显的 4.9 倍缺陷（P < 0.001）。主动接种 rPbSEA-1 可使寄生虫血症减少 3.9 倍，伯氏疟原虫 ANKA 寄生虫攻击后存活率延长 2 倍（P = 0.001）。与抗体水平可检测到的时期（0 例/1,688 儿童周；调整后 OR 4.4）相比，坦桑尼亚队列中的儿童在抗 PfSEA-1 抗体水平无法检测到的时期（45 例/23,806 儿童周）经历了严重疟疾的发病率显着增加。 ; III 型固定效应 P < 0.01)。在我们的肯尼亚队列中，与未检测到抗 PfSEA-1 抗体的个体相比，具有可检测到的抗 PfSEA-1 抗体的青少年和年轻人的寄生虫血症降低了 50%。这些结果首次证明特异性阻断裂殖体流出的抗体可以预防人类严重疟疾，并表明 PfSEA-1 可能与针对肝细胞和红细胞侵袭的疫苗产生协同作用。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 3- 统称为 MSP）和 PfGARP（一种以前未被识别的候选疫苗，仅在恶性疟原虫中发现）。在体外测定中，多克隆抗 MSP-4 可抑制寄生虫生长 22% (P < 0.001)，与抗 PfSEA-1 mAb 联合使用时，这种抑制作用增加至 67% (P < 0.001)。与对照相比，PfGARP 高度不变的羧基末端抗体（PfGARP-A，aa 411-673）通过阻止滋养体发育，在体外抑制寄生虫生长 99%（P < 0.001）。在此应用中，我们将在鼠类疫苗试验中评估这些候选疫苗在多种佐剂中的组合，并将在非人类灵长类动物中进一步评估先导组合。这项研究的成果将是一种佐剂优化的三价疫苗，其目标是寄生虫从单一关键寄生虫阶段进入、细胞内发育和退出。