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

项目总结 疟疾每年折磨着2亿多人，其中疟疾寄生虫恶性疟原虫是 2018年约40.5万人死于疟疾，其中绝大多数是罪魁祸首。一种高效的疟疾疫苗是 被广泛视为在流行地区减少疟疾的迫切需要的工具，在那里提供医疗保健和 病媒控制战略经常受到政治冲突、自然灾害和迅速流行的疾病的干扰。 可传播的病毒。针对红细胞前抗原和全子孢子免疫的疫苗 方法的目的是诱导无菌免疫，以防止肝期感染的进展，从而 建立寄生虫血症和临床疟疾。然而，第一种获得许可的疟疾疫苗，针对的是 红细胞前环子孢子蛋白在预防非洲严重疟疾方面只有部分效果 婴儿。在多阶段疟疾疫苗中加入无性血液期抗原可以提高疟疾疫苗的效力 通过减轻突破性寄生虫血症引起的临床疾病，第一代疫苗部分有效。 几种有希望的血液阶段抗原已经在临床试验中被优先考虑，但对 考虑到实现实地研究的挑战，疟疾疫苗开发流程中的其他抗原是谨慎的 对一种遗传多样性寄生虫的疗效。在我们的初步研究中，我们发现抗体反应 抗两种不同恶性疟原虫的抗原在一组受疟疾保护的儿童中显著增加 在马里进行的一项纵向队列研究中，与易患疟疾的儿童有关。我们建议评估 通过测定这两种恶性疟原虫抗原作为疟疾疫苗候选疫苗的天然获得性免疫球蛋白 针对这些蛋白的抗体可以预测疟疾在较大的父母队列中的保护作用，并对 寄生活动。我们的假设是，这两种抗原中的保守区域都是天然 获得对恶性疟疾的保护性免疫。为了检验这一假设，我们将确定基因 在编码这些寄生虫抗原的基因内，当地恶性疟原虫田间分离株的多样性，这将使 US以确定重组蛋白表达的保守区。然后我们将确定自然获得的 针对每个抗原内保守区的抗体反应可以预测对疟疾的保护作用 亲代队列研究以及这些抗体是否具有体外抗恶性疟原虫活性。 该项目的成功完成将为了解这两种抗原的遗传多样性和 提供证据证明这些抗原中的保守区是否是自然获得性 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.