Assessing the role of liver stage antigens-specific antibodies against Plasmodium falciparum liver stage infection

评估肝期抗原特异性抗体对抗恶性疟原虫肝期感染的作用

• 批准号: 10392870
• 负责人: Urszula Krzych
• 金额: $ 28.29万
• 依托单位: HENRY M. JACKSON FDN FOR THE ADV MIL/MED
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-15 至 2024-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10392870
• 关键词: Activities of Daily Living; Antibodies; Antibody Formation; Antibody Response; Antigens; Antimalarials; Biological; Biological Assay; Blood; Clinical; Clinical Trials; Communicable Diseases; DNA; Development; Erythrocytes; Funding Agency; Generations; Goals; Hepatocyte; Human; Immune; Immune system; Immunize; Immunofluorescence Immunologic; In Vitro; Inbred BALB C Mice; Infection; Kinetics; Kupffer Cells; Life Cycle Stages; Liver; Malaria; Measures; Mediating; Methods; Mission; Modeling; Monoclonal Antibodies; Mus; Organ; Outcome; Parasites; Pathogenicity; Pathway interactions; Phagocytes; Plague; Plasmodium; Plasmodium falciparum; Preventive measure; Production; Prophylactic treatment; Proteins; Reagent; Role; Specificity; Sporozoites; Sterility; Surface; Testing; Vaccines; assay development; base; biological development; circumsporozoite protein; design; efficacy testing; human monoclonal antibodies; immunogenicity; improved; malaria infection; monoclonal antibody production; mouse model; novel; novel strategies; prevent; prophylactic; protective efficacy; tool

PROJECT SUMMARY The recent discovery of Plasmodium falciparum (Pf) liver stage antigens (LS Ags) is providing us with an opportunity for conducting explorations of the utility of these Ags as vehicles to prevent malaria and also as tools for seeking a better understanding of the Plasmodium LS development. Amongst the Plasmodium spp., Pf remains one of the deadliest infectious diseases that plagues many parts of the world and anti-malaria approaches are not fully effective. Currently, these approaches have been shifting towards the development of human monoclonal antibodies (hmAbs) as a more effective anti-malaria measure. Clinical trials are underway with hmAbs directed to a single target, the circumsporozoite protein (CSP). It is likely that similar to CSP- based RTS,S vaccine, mAbs directed to a single Ag, the CSP, may be insufficient to prevent malaria. Even a single spz that escapes anti-CSP Abs will infect hepatocytes and initiate clinical malaria. We are proposing an alternative strategy that may improve the CSP-based preventative measures. We would incorporate Ags expressed during the Plasmodium LS development. We hypothesize that a combination of Ags that includes CSP and LS Ags would provide a broader Ab specificities and a wider coverage against the parasite. We have previously demonstrated in a mouse model that P. berghei and P. yoelii LS Ags, orthologues of Pf LS Ags, reduce liver parasite burden (LPB) following spz challenge. When co-administered with Pb CSP, some Pb LS Ags induced sterile protection in 80% as compared with ~40% protection of mice that received only Pb CSP or a combination of the 3 Pb LS Ags. Like CSP, the Pb LS Ags induced antibody responses to Ags on spz and infected hepatocytes. On the basis of these results we hypothesize that a cocktail of mAbs specific for targets on CSP and LS Ags is needed for an efficacious approach to prevent malaria. The availability of the humanized DRAGA mouse - with its developed functional human immune system, human hepatocytes, Kupffer cells, and erythrocytes, which allow complete vertebrate Pf life cycle - presents an ideal model for (1) producing Pf LS Ags-specific hmAbs and (2) subsequently for testing the efficacy of a cocktail of Pf CSP- and LS Ag-specific hmAbs in preventing malaria infection after Pf spz challenge. The successful production Pf LS Ags-specific hmAbs could be used to enhance protection mediated by CSP; these hmAbs also would provide reagents needed towards explorations of the mechanism of liver pathogenicity as well as organ-specific immunogenicity of Plasmodium LS Ags.

项目摘要 恶性疟原虫（Plasmodiumfalciparum，Pf）肝期抗原（LSAgs）的发现为我们提供了 有机会进行探索的效用，这些ag作为车辆，以防止 疟疾，也作为寻求更好地了解疟原虫LS发展的工具。 在疟原虫属中，Pf仍然是困扰人类的最致命的传染病之一 在世界许多地区，防治疟疾的方法并不完全有效。目前这些 方法已经转向开发人单克隆抗体 （hmAbs）作为更有效的抗疟疾措施。hmAbs的临床试验正在进行中 针对单一靶标环子孢子蛋白（CSP）。这可能与CSP类似- 基于RTS，S疫苗，针对单一Ag的mAb，CSP，可能不足以预防 疟疾即使是一个逃避抗CSP抗体的spz也会感染肝细胞并启动临床试验。 疟疾我们提出了一种替代策略，可以改善基于CSP的预防性治疗。 措施我们将掺入疟原虫LS发育期间表达的Ag。我们 假设包括CSP和LS Ag的Ag组合将提供更广泛的 抗体特异性和更广泛的覆盖面对寄生虫。我们之前已经在 伯氏疟原虫和约氏疟原虫LS Ags（Pf LS Ags的直系同源物）降低肝脏的小鼠模型 SPZ攻毒后的寄生虫负荷（LPB）。当与铅CSP联合给药时，一些铅LS Ags诱导的不育保护率为80%，而接受Ags的小鼠的保护率为40%。 仅Pb CSP或3种Pb LS Ag的组合。与CSP一样， SPZ和感染的肝细胞对Ag的反应。根据这些结果，我们假设 需要对CSP和LS Ag上的靶标具有特异性的mAb的混合物来有效地治疗CSP和LS Ag上的靶点。 预防疟疾的方法。人源化DRAGA小鼠的可用性-其 开发功能性人类免疫系统、人类肝细胞、枯否细胞， 红细胞，它允许完整的脊椎动物Pf生命周期-提出了一个理想的模型（1） 产生Pf LSAgs特异性hmAb和（2）随后用于测试以下物质的混合物的功效： Pf CSP和LS Ag特异性hmAb在Pf spz攻击后预防疟疾感染。的 成功生产Pf LSAgs特异性hmAb可用于增强Pf LSAgs介导的保护作用。 这些hmAbs也将提供探索人类免疫系统所需的试剂。 疟原虫LS的肝脏致病机制及器官特异性免疫原性 艾格斯