Defining targets of protective immunity in Plasmodium vivax using human monoclonal antibodies

使用人单克隆抗体确定间日疟原虫保护性免疫的目标

• 批准号: 10651591
• 负责人: Christopher L King
• 金额: --
• 依托单位: LOUIS STOKES CLEVELAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10651591
• 关键词: Affinity Chromatography; Animals; Antibodies; Antibody Therapy; Antigen Receptors; Antigens; Aotus primate; Area; Australia; B-Lymphocytes; Beds; Binding; Binding Proteins; Blocking Antibodies; Blood; Cambodia; Chronic; Chronic Disease; Clinical; Collaborations; Communicable Diseases; Country; Crystallization; Culicidae; Data; Development; Disease; Drug resistance; Epitopes; Erythrocytes; Erythroid Cells; Exposure to; Generations; Geographic Locations; Geography; Goals; Health Policy; Human; Human Resources; Immune response; Immunity; Immunoglobulin G; In Vitro; Individual; Infection; Infectious Diseases Research; Invaded; Life Cycle Stages; Ligands; Liver; Malaria; Mediating; Medical center; Military Personnel; Modeling; Monitor; Monkeys; Monoclonal Antibodies; Morbidity - disease rate; Nature; Outcome; Parasitemia; Parasites; Peru; Phase; Plasmodium falciparum; Plasmodium vivax; Plasmodium vivax vaccine; Population; Primates; Production; Prophylactic treatment; Protein Sortings; Proteins; Public Health; Recombinant Proteins; Relapse; Research; Residual state; Reticulocytes; Risk; Risk Reduction; Scientist; Seasons; Serum; Soldier; Sporozoites; Syndrome; TFRC gene; Testing; Transcend; United States Department of Veterans Affairs; Universities; Vaccines; Veterans; Vivax Malaria; acquired immunity; active duty; asexual; chemokine receptor; clinical risk; experience; experimental study; global health; human monoclonal antibodies; in vivo; inhibiting antibody; malaria infection; mortality; mosquito-borne; nanobodies; nonhuman primate; novel; novel therapeutics; programs; receptor; standard measure; transmission process; vaccine candidate; vaccine development; vaccine strategy

Plasmodium vivax (Pv) is a major cause of malaria worldwide and frequently results in illness among active duty military personnel. It is also an important cause of malaria in veterans because the parasite develops a latent stage of infection that can relapse years later. Our aim is to develop a vaccine and novel therapeutics for Pv. The goal for vaccine development efforts is a multi-component vaccine that targets multiple stages of the Pv life cycle in humans. In this proposal, our focus is on two essential Pv proteins required for parasitic invasion of red blood cells (in this case, reticulocytes). These are the Duffy Binding Protein (DBP) and the Reticulocyte Binding Protein 2b (RBP2b). Our approach is to generate human monoclonal antibodies (mAbs) from individuals with naturally-acquired immunity to Pv. Using B cells from donors with robust immune responses, we will identify B cells specific for DBP and RBP2b and generate mAbs against these two essential invasion proteins. We will test whether the mAbs can block the binding of Pv proteins to their receptors on reticulocytes and if so, whether they can inhibit Pv invasion of reticulocytes in vitro. We will then determine which Pv protein targets (epitopes) are recognized by the most effective mAbs. We will identify the mAb targets that are likely to be present in Pv strains globally and thus useful for inclusion in a pan-global vaccine. The most promising mAbs will then be tested for their ability to protect against Pv blood stage infection in an Aotus monkey model of Pv infection. Working with our collaborators at the NAMRU-6 primate unit in Peru, mAbs will be passively transferred to Aotus monkeys and the animals monitored for protection against Pv malaria. Pending the outcome of our animal protection experiments, we will proceed with further development of a vaccine candidate (an immunogen) that incorporates the essential Pv targets identified. We will use a novel animal-based approach to generate stable immunogens known as nanobodies or VHH antibodies. Our studies will involve a carefully orchestrated collaboration by experienced scientists working on malaria at the Veterans Affairs Medical Center in Cleveland, OH; Center for Global Health and Diseases at Case Western Reserve University in Cleveland, OH; Malaria Unit, Institute Pasteur, Cambodia; Walter and Eliza Hall Institute, Australia; and the NAMRU-6 unit in Peru. Our results will enable progress toward a multi-component vaccine against Pv. They will also advance the potential of antibody therapies for severely ill individuals and those in need of sustained prophylaxis during seasonal transmission and tours of duty. !

Vivax疟原虫（PV）是全球疟疾的主要原因，并且经常导致活跃的疾病 值班军事人员。这也是退伍军人疟疾的重要原因，因为寄生虫会发展 潜在的感染阶段可能会在几年后复发。我们的目的是开发一种疫苗和新颖的治疗剂 对于PV。疫苗开发工作的目标是一种多组分疫苗，其针对多个阶段 人类的光伏生命周期。在此提案中，我们的重点是寄生所需的两种必需的PV蛋白 红细胞的侵袭（在这种情况下为网状细胞）。这些是达菲的结合蛋白（DBP）和 网状细胞结合蛋白2B（RBP2B）。我们的方法是生成人类单克隆抗体（mAb） 从具有自然获得免疫力的个体到PV。使用具有强大免疫供体的B细胞 响应，我们将识别针对DBP和RBP2B的B细胞，并针对这两个必需 入侵蛋白。我们将测试mAb是否可以阻止PV蛋白与其受体的结合 网状细胞以及如果是这样，它们是否可以抑制体外的网状细胞的PV侵袭。然后我们将确定 哪些PV蛋白靶标（表位）被最有效的mAB识别。我们将确定mAb目标 这些可能存在于全球PV菌株中，因此可用于包含在泛全球疫苗中。这 然后，最有前途的mAb将测试其防止AOTUS中PV血液阶段感染的能力 光伏感染的猴子模型。与我们在秘鲁Namru-6灵长类动物部门的合作者合作，mabs将 被动地转移到Aotus猴子，并监测的动物以防止PV疟疾。 在我们的动物保护实验的结果之前，我们将进一步发展 候选疫苗候选者（一种免疫原），其中包含所鉴定的必需PV靶标。我们将使用小说 基于动物的方法来产生稳定的免疫原子，称为纳米剂或VHH抗体。我们的研究 将涉及经验丰富的科学家精心策划的合作，从事退伍军人的疟疾 俄亥俄州克利夫兰事务医疗中心； Case Western Reserve的全球健康与疾病中心 俄亥俄州克利夫兰的大学；柬埔寨的疟疾单位，疟疾；沃尔特和伊丽莎·霍尔学院 澳大利亚;和秘鲁的Namru-6单元。我们的结果将使多组分疫苗的进展 反对PV。他们还将提高严重患者和其中的抗体疗法的潜​​力 在季节性传播和值班之旅中需要持续预防。 呢