RBL Binding Domain Malaria Candidate Vaccines

RBL 结合域疟疾候选疫苗

• 批准号: 8104854
• 负责人: MARY R GALINSKI
• 金额: $ 30.8万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8104854
• 关键词: Antibodies; Antigen Targeting; Antigens; Antimalarials; Apical; Attention; Attenuated; Binding; Binding Proteins; Biological; Biological Process; Blood; COS Cells; Categories; Cell Adhesion Molecules; Cessation of life; Clinical Trials; Data; Development; Drug Formulations; Ensure; Erythrocytes; Escherichia coli; Family; Funding; Future; Gene Proteins; Genes; Homologous Gene; Human; Immune; Immune Sera; Immune response; Immunization; In Vitro; Infection; Intervention; Invaded; Investigation; Knowledge; Laboratories; Learning; Legal patent; Ligands; Macaca mulatta; Malaria; Malaria Vaccines; Modeling; Monkeys; N-terminal; Outcome; Parasitemia; Parasites; Pharmaceutical Preparations; Plasmodium; Plasmodium falciparum; Plasmodium knowlesi; Preparation; Process; Protein Family; Proteins; Recombinant Proteins; Recombinants; Research; Reticulocytes; Role; Staging; Surface; System; Testing; Time; Trefoil Motif; Vaccination; Vaccine Antigen; Vaccines; Validation; Vivax Malaria; Work; base; efficacy testing; immunogenicity; improved; innovation; interest; nonhuman primate; novel strategies; novel vaccines; pre-clinical; preclinical study; prevent; sound; tool; vaccine candidate; vaccine development; vaccine evaluation

DESCRIPTION (provided by applicant): This exploratory R21 proposal focuses on evaluating two Reticulocyte Binding-Like (RBL) protein vaccine candidates in rhesus monkeys with a blood-stage challenge to test for efficacy, providing for the first-time a proof of principle for this category of merozoite vaccine antigens, and also preparing P. vivax RBL antigens for future pre-clinical trials. Plasmodium knowlesi blood-stage infections in rhesus macaques become lethal 1-2 weeks after inoculation unless treated with anti-malarial drugs. We are proposing to test the potential of P. knowlesi RBL binding domains to function as immunogens that will attenuate the usual lethality of this parasite. If protection can be achieved against a conserved key biological target in monkeys, like the RBLs, there can be heightened confidence for advancing the homologous P. falciparum and P. vivax target(s) as a vaccine(s) in clinical trials. This project builds upon this group's discovery of the P. vivax Reticulocyte Binding Proteins (PvRBPs), the subsequent identification of these proteins in other species, (P. falciparum, P. cynomolgi, P. coatneyi, P. reichenowi, and P. knowlesi), and the identification and preparation as immunogens of two P. knowlesi RBL binding domains. The RBL proteins (also known as the reticulocyte-binding homologue (RH) protein superfamily) are located at the apical pole of merozoites, bind erythrocytes and are believed to be instrumental in directing merozoite invasion. Multiple rbl genes exist in each Plasmodium species (with only 2 in P. knowlesi, yet as many as 14 in P. yoelii), and data suggests that each species has maintained the ability to use one or another of the encoded ligands, or possibly combinations, as adhesion molecules to ensure entry into red blood cells. Critically, each species appears to have at least two RBLs that are essential for merozoite invasion. In Aim 1 using a rhesus monkey model we propose to test the hypothesis that immunization with an RBL red blood cell binding domain can limit a lethal infection, and that the combination of multiple RBL binding domain regions will provide greater protection. In Aim 2, we will test the hypothesis that antisera to homologous binding domain regions from P. vivax RBL proteins will inhibit invasion of merozoites in vitro, as a prelude to possible pre-clinical vaccine trials using these proteins in NHPs. We will work to optimize the expression and purification of homologous binding domain regions from expressed P. vivax RBL proteins, characterize functionality (i.e. binding), develop and test the ability of these RBLs or specific antisera to inhibit invasion in vitro. Regardless of the outcome from vaccine testing, we will have gained knowledge and additional tools to study the RBLs as critical ligands for red blood cell invasion and as possible biological targets of intervention. PUBLIC HEALTH RELEVANCE: A malaria vaccine would be extremely valuable tool to help control malaria. Novel approaches and new paradigms are needed that can expedite the testing and provide some form of validation for theoretically sound malaria vaccine candidates. This proposal is straightforward, while also being innovative, risky and exploratory. We will learn whether RBL-based malaria vaccines can provide protection against erythrocytic challenge and also develop valuable tools for advancing investigations relating to merozoite invasion of red blood cells. This research will also gain valuable information on the immune response to the RBLs and pave the way for potential pre- clinical malaria vaccine trials based on P. vivax RBL immunogens.

DESCRIPTION (provided by applicant): This exploratory R21 proposal focuses on evaluating two Reticulocyte Binding-Like (RBL) protein vaccine candidates in rhesus monkeys with a blood-stage challenge to test for efficacy, providing for the first-time a proof of principle for this category of merozoite vaccine antigens, and also preparing P. vivax RBL antigens for future pre-clinical trials.在接种后1-2周，猕猴中的氏疟原虫血液阶段感染已致死1-2周，除非用抗疟疾药物治疗。我们提议测试诺尔斯疟原虫RBL结合结构域的潜力，使其充当免疫原子，从而减弱该寄生虫的常规致死性。如果可以在像RBL这样的猴子中对猴子中保守的关键生物学靶标获得保护，则可以提高信心，以推进临床试验中的疫苗，将同源性恶性疟原虫和维瓦克斯假单胞菌靶标作为疫苗。 This project builds upon this group's discovery of the P. vivax Reticulocyte Binding Proteins (PvRBPs), the subsequent identification of these proteins in other species, (P. falciparum, P. cynomolgi, P. coatneyi, P. reichenowi, and P. knowlesi), and the identification and preparation as immunogens of two P. knowlesi RBL binding domains. RBL蛋白（也称为网状细胞结合同源物（RH）蛋白超家族）位于Merozoite的顶端，结合红细胞，据信在指导Merozoite侵袭中具有重要作用。每个疟原虫物种中都存在多个RBL基因（在P. knewlesi中只有2个，但在P. yoelii中只有14个），数据表明，每个物种都保持了使用一种或另一种编码的配体或可能组合的能力，或者可能组合，作为粘附分子确保进入红细胞。至关重要的是，每个物种似乎至少有两个RBL，这对于梅龙伊特入侵必不可少。在使用恒河猴模型的AIM 1中，我们建议测试以RBL红细胞结合结构域免疫的假设可以限制致命感染，并且多个RBL结合域区域的组合将提供更大的保护。在AIM 2中，我们将检验以下假设：抗血清蛋白质蛋白的抗血清与同源结合结构域区域将抑制体外的梅罗洛罗兹氏菌的侵袭，这是使用NHP中可能使用这些蛋白质的临床前疫苗试验的前奏。我们将致力于优化来自表达的息肉杆菌RBL蛋白的同源结合结构域区域的表达和纯化，它表征了功能（即结合），发展和测试这些RBL或特定抗血清在体外抑制浸润的能力。无论疫苗测试的结果如何，我们都将获得知识和其他工具，以研究RBL作为红细胞侵袭的关键配体，以及作为干预的可能生物学靶标。 公共卫生相关性：疟疾疫苗将是帮助控制疟疾的极其有价值的工具。需要新颖的方法和新的范式，可以加快测试并为理论上声音疟疾疫苗候选者提供某种形式的验证。该提议很简单，同时也具有创新，风险和探索性。我们将了解基于RBL的疟疾疫苗是否可以提供防止红细胞挑战的保护，还可以开发有价值的工具来推进与红细胞梅洛祖特入侵有关的研究。这项研究还将获得有关对RBL的免疫反应的宝贵信息，并为基于Vivax P. vivax RBL免疫原子的潜在前临床疟疾疫苗试验铺平道路。