Validation and characterization of antibody responses to Plasmodium falciparum antigens identified by protein array screening

项目摘要 疟疾每年折磨着2亿多人，疟疾寄生虫恶性疟原虫是一种寄生虫。 造成2018年约40.5万例疟疾死亡的绝大多数。一种高效的疟疾疫苗 被广泛认为是在流行地区减少疟疾的急需工具， 病媒控制战略经常因政治冲突、自然灾害和迅速蔓延的流行病而中断， 传染性病毒靶向红细胞前抗原的疫苗和全子孢子免疫 这些方法旨在诱导无菌免疫，以防止肝脏阶段感染的进展， 寄生虫血症和临床疟疾的建立。然而，第一种获得许可的疟疾疫苗， 红细胞前环子孢子蛋白，在预防非洲严重疟疾方面仅部分有效 婴儿。在多阶段疟疾疫苗中包含无性血液阶段抗原可以提高 部分有效的第一代疫苗通过减轻由突破性寄生虫血症引起的临床疾病。 几种有前途的血液阶段抗原已在临床试验中优先考虑，但对 考虑到在疟疾疫苗开发管道中实现实地应用的挑战， 对遗传多样性寄生虫的有效性。在我们的初步研究中，我们发现抗体反应 抗两种不同的恶性疟原虫抗原的抗体在一个疟疾保护儿童亚组中显著增加 在马里进行的一项纵向队列研究中，我们建议评估 这两种恶性疟原虫抗原作为疟疾疫苗候选物， 针对这些蛋白质的抗体可以预测在较大的父母群体中的疟疾保护， 寄生活动我们的假设是，任一抗原中的保守区域是天然免疫应答的靶点。 获得对恶性疟疾的保护性免疫。为了验证这一假设，我们将确定基因 在编码这些寄生虫抗原的基因内的当地恶性疟原虫田间分离株的多样性，这将允许 我们鉴定了重组蛋白表达的保守区域。然后我们将确定是否自然获得 针对每种抗原内保守区的抗体应答可以预测在小鼠中对疟疾的保护作用。 亲本队列研究以及这些抗体是否具有体外抗恶性疟原虫的活性。 该项目的成功完成将提供对这两种抗原的遗传多样性的深入了解， 提供了这些抗原中的保守区域是否是天然获得性免疫缺陷病毒的靶点的证据。 对疟疾的保护性免疫。

PROJECT SUMMARY Malaria afflicts more than 200 million people yearly, with the malaria parasite Plasmodium falciparum being responsible for the vast majority of the ~405,000 malaria deaths in 2018. A highly effective malaria vaccine is widely viewed as a much-needed tool for reducing malaria in endemic areas where healthcare delivery and vector control strategies are often disrupted by political conflict, natural disasters, and epidemics of rapidly transmissible viruses. Vaccines that target pre-erythrocytic antigens and whole sporozoite immunization approaches aim to induce sterile immunity that prevents the progression of liver-stage infection and thus the establishment of parasitemia and clinical malaria. However, the first licensed malaria vaccine, which targets the pre-erythrocytic circumsporozoite protein, is only partially effective at preventing severe malaria in African infants. Inclusion of asexual blood-stage antigens in a multi-stage malaria vaccine could improve the efficacy of partially effective first-generation vaccines by mitigating clinical disease caused by breakthrough parasitemia. Several promising blood-stage antigens have been prioritized in clinical trials, but the continued evaluation of other antigens in the malaria vaccine development pipeline is prudent given the challenges of achieving field efficacy against a genetically diverse parasite. In our preliminary studies, we found that antibody responses against two distinct P. falciparum antigens were significantly increased in a subset of malaria-protected children relative to malaria-susceptible children in a longitudinal cohort study conducted in Mali. We propose to evaluate these two P. falciparum antigens as malaria vaccine candidates by determining whether naturally acquired IgG antibodies against these proteins can predict malaria protection in the larger parent cohort and exert anti- parasitic activity. Our hypothesis is that conserved regions within either antigen are the targets of naturally acquired protective immunity against falciparum malaria. To test this hypothesis, we will determine the genetic diversity of local P. falciparum field isolates within the genes encoding these parasite antigens, which will allow us to identify a conserved region for recombinant protein expression. We will then determine if naturally acquired antibody responses against the conserved region within each antigen can predict protection from malaria in the parent cohort study and whether these antibodies have activity against P. falciparum parasites in vitro. Successful completion of this project will provide insight on the genetic diversity of these two antigens and provide evidence as to whether conserved regions within these antigens are the targets of naturally acquired protective immunity against malaria.