PfSEA-1 based vaccines for falciparum malaria

基于 PfSEA-1 的恶性疟疾疫苗

• 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
• 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

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进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感染数亿人，造成100多万儿童死亡。在之前R01资助的研究中，我们确定了自然获得的保护性人类抗体的寄生虫靶点。我们利用来自坦桑尼亚一组出生儿童的血浆和流行病学数据，应用我们的差异全蛋白质组筛选方法，鉴定两岁儿童中与耐药性相关的新型恶性疟原虫抗原。这项工作最终在《科学》杂志上发表了一篇全面、完整的研究文章。我们发现裂体出口抗原-1 （pfse1）是一种244kda的寄生虫抗原，定位于裂体感染红细胞的裂体/寄生液泡膜、毛雷尔裂隙和红细胞膜内小叶。PfSEA-1中心高度不变性的274aa区抗体（rPfSEA-1A, a810 - 1083）通过阻止分裂体破裂，使三种寄生虫株的寄生虫复制比对照组减少58-75%（均P < 0.009）。在基因不稳定实验中，PfSEA- 1不稳定的寄生虫在寄生虫复制上有明显的4.9倍缺陷（P < 0.001）。活疫苗接种rPbSEA-1可使寄生虫血症降低3.9倍，使伯氏假单胞杆菌ANKA寄生虫攻毒后的存活时间延长2倍（P = 0.001）。坦桑尼亚队列中的儿童在抗pfsea -1抗体水平检测不到的时期（45例/23,806儿童周）与抗体水平检测到的时期（0例/1,688儿童周；调整OR 4.4； III型固定效应P < 0.01）相比，严重疟疾的发病率显著增加。在我们的肯尼亚队列中，检测到抗pfsea -1抗体的青少年和年轻人的寄生虫率比未检测到抗pfsea -1抗体的个体低50%。这些结果首次证明，特异性阻断分裂体出口的抗体可以预防人类严重疟疾，并表明PfSEA-1可能与靶向肝细胞和红细胞入侵的疫苗协同作用。我们的疫苗发现项目还发现了几种已知的入侵配体（MSP-4和MSP-7 - 3-统称为msp）和PfGARP，这是一种以前未被识别的候选疫苗，仅在恶性疟原虫中发现。在体外实验中，多克隆抗msp -4对寄生虫生长的抑制作用为22% (P < 0.001)，与抗pfsea -1 mAb联合使用时，抑制作用增加到67% （P < 0.001）。PfGARP高度不变的羧基末端的抗体（PfGARP- a, aa 411-673）通过阻止滋养体的发育，在体外抑制寄生虫生长的效果比对照组高99% （P < 0.001）。在此申请中，我们将在小鼠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的、关键的寄生虫状态进入、细胞内发育和退出。